During this early in-hospital phase, therapy is primarily aimed at stabilizing the patient by stabilizing the culprit coronary lesion and thus preventing a recurrence of myocardial ischemia at rest and progression to MI.
Patients whose history is compatible with a diagnosis of unstable angina should be promptly hospitalized in an intensive or intermediate care unit. General supportive care includes bed rest with continuous monitoring of cardiac rate and rhythm and frequent evaluation of vital signs; relief of anxiety with appropriate reassurance and, if necessary, anxiolytic medication; and treatment of associated precipitating or aggravating factors such as hypoxia, hypertension, dysrhythmias, heart failure, acute blood loss, or thyrotoxicosis. A 12-lead ECG should be repeated if it is initially unrevealing or if any significant change has occurred in symptoms or clinical stability. Serial cardiac biomarker evaluation should be performed as a part of an NSTEMI rule-out protocol and to evaluate the extent of myocardial damage and used for outcome risk stratification.
Outcome Risk Stratification
The Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk scores are the two commonly used risk scores to predict short-term risk of events and are helpful for clinical decision making. GRACE score is calculated based on the sum of the scores assigned to clinical parameters such as age, heart rate, systolic blood pressure, serum creatinine, Killip classification, presence of cardiac arrest, ST segment deviation, and elevation of cardiac enzymes. The score predicts outcome events reasonably well both in test and validation cohorts, predicting greater than 3% in-hospital death with a score higher than 140. Calculation of GRACE score is somewhat complex, but an online version of the GRACE risk score calculator is available at www.outcomes.org/grace. The TIMI score contains less clinical variables with 1 point assigned to each variable; hence, it is easier for clinical usage and performs relatively well in predicting outcome. However, the TIMI score lacks several key factors compared to the GRACE score, and thus is not as accurate in predicting outcomes as the GRACE score. The TIMI calculator is available at www.timi.org.
Nitrates are generally considered one of the cornerstones of therapy (Table 7–3); however, their use is largely based on clinical experience, not on randomized clinical trials. Nitrates relieve and prevent ischemia by improving subendocardial blood flow in the ischemic zone through their vasodilator actions, predominantly on the large epicardial vessels, including the stenotic segments and the coronary collaterals. Nitrates directly stimulate cyclic guanosine monophosphate (GMP) production, achieving vasodilatory effect in the vascular smooth muscle without requiring an intact or functional endothelium; hence, their effects are generally well preserved in atherosclerosis. Reduction of left ventricular preload and afterload by peripheral vasodilator actions may contribute to the reduction of myocardial ischemia. Although nitrates may reduce the number of both symptomatic and asymptomatic episodes of myocardial ischemia in unstable angina, no effect has yet been demonstrated on the incidence of progression to MI or death.
Table 7–3. Effects of Medical Therapy in USA/NSTEMI ||Download (.pdf)
Table 7–3. Effects of Medical Therapy in USA/NSTEMI
Progression to Acute Myocardial Infarction
Calcium channel blockers
In the very acute phase, it is preferable to use intravenous nitroglycerin to ensure adequate bioavailability, a rapid onset and cessation of action, and easy titration of doses. Oral, sublingual, transdermal, and transmucosal preparations are better suited for subacute and chronic use. To minimize the chances of abrupt hypotension, nitroglycerin infusion should be started at 10 mcg/min and the infusion rate titrated according to symptoms and blood pressure. The goal is to use the lowest dose that will relieve ischemic symptoms without incurring side effects. The side effects of nitrates include hypotension, reflex tachycardia associated with hypotension; occasional profound bradycardia, presumably related to vagal stimulation; headaches; and facial flushing. Rare side effects include methemoglobinemia, alcohol intoxication, and an increase in intraocular and intracranial pressure. Because the magnitude of reduced arterial pressure that a patient can tolerate without developing signs of organ hypoperfusion varies, it is difficult to define an absolute cut-off point. A reasonable approach in normotensive patients without heart failure is to maintain the arterial systolic blood pressure no lower than 100–110 mm Hg; in hypertensive patients, reduction below 120–130 mm Hg may be unwise.
Continuous and prolonged administration of intravenous nitroglycerin for more than 24 hours may lead to the attenuation of both its peripheral and coronary dilator actions. This effect is due to the development of tolerance in some patients. At the present time, however, there is no easy and practical way to avoid or overcome this problem other than escalating the dose to maintain reduction in measurable end points (eg, the arterial blood pressure).
With the increasing use of phosphodiesterase-5 inhibitors (such as sildenafil) for erectile dysfunction among patients with coronary artery disease or the recreational use of such medication, it is important to obtain a history of whether the patient has taken such medication 24 hours prior to presentation of USA/NSTEMI. Nitrate-mediated vasodilation in the presence of phosphodiesterase-5 inhibition can lead to prolonged hypotension or even death.
The evidence for use of β-blockers in USA/NSTEMI extrapolates mostly from studies in STEMI or stable angina patients. Use of β-blockers has been shown to reduce the frequency of both symptomatic and asymptomatic ischemic episodes in stable as well as unstable angina. These protective effects are generally attributed to their negative chronotropic and inotropic effects, which reduce the imbalance of myocardial oxygen demand and supply. Their ability to reduce the risk of infarct development is less clear, but they do decrease reinfarction and mortality rates in postinfarction patients. The mechanism of their protective effect against reinfarction remains unexplained, although it has been speculated that they reduce the risk of plaque rupture by reducing mechanical stress on the vulnerable plaque. It is also unclear whether β-blockers offer any additional benefit in unstable angina patients who are already receiving nitrates and antiplatelet-anticoagulant therapy.
β-blockers administered orally, not intravenously, can be started early (within 24 hours after admission) in the absence of contraindications such as congestive heart failure, hemodynamic instability, heart block, or active reactive airway disease. The choice of β-blockers depends on pharmacokinetic consideration as well as physician familiarity; however, β-blockers without intrinsic sympathomimetic activity, such as propranolol, atenolol, or metoprolol, are preferred.
Calcium channel blockers are also frequently used in managing ischemic heart disease. Their beneficial effects in myocardial ischemia are generally attributed to their ability to improve myocardial blood flow by reducing coronary vascular tone and dilation of large epicardial vessels and coronary stenoses through an endothelium-independent action. They also reduce myocardial workload through their negative chronotropic (diltiazem and verapamil) and inotropic and peripheral vasodilator effects. Because exaggerated vasoconstriction may play a role in unstable angina, calcium channel blockers have been used in its management. In general, although calcium channel blockers have been shown to reduce the frequency of ischemic episodes in unstable angina, their protective effect against the development of acute MI has not been definitively demonstrated. In fact, the use of such calcium channel blockers as nifedipine tends to increase the risk of ischemic complications in unstable angina. Such adverse effects may well be due to reflex tachycardia or coronary steal caused by the arteriole-dilating actions of dihydropyridine calcium channel blockers. The protective effects of the heart rate-slowing calcium channel blocker diltiazem have been reported in patients with a non-Q wave MI and preserved ventricular function. As in the case of β-blockers, the additive benefits of calcium channel blockers in patients with unstable angina who are receiving nitrates and antithrombotic therapy have not been defined, and their use should also be considered an adjunct to such drugs.
Platelet activation and aggregation leading to coronary thrombosis is the hallmark feature underlying the pathophysiology of acute coronary syndrome. Hence, inhibition of platelet activation via pharmacologic blockade of signaling pathways such as cyclooxygenase-1 or P2Y12 receptor plays a central role in managing acute coronary syndrome.
Aspirin irreversibly inhibits cyclooxygenase-1 and reduces thromboxane A2 production; hence, it reduces platelet aggregation by this pathway. It has been shown to reduce the risk of developing MI by about 50% in at least four randomized trials. The protective effect of aspirin in unstable angina has been comparable, in the dosage range of 75–1200 mg/day. Because of the potential for gastrointestinal side effects, low doses of aspirin (75–81 mg/day) are preferable for daily maintenance. A higher loading dose of 160–325 mg on the first day is recommended in order to initiate the antiplatelet effect more rapidly.
P2Y12 Receptor Inhibitors
Adenosine diphosphate (ADP) is one of the inducers of platelet activation by binding to a G-protein–coupled P2Y12 receptor with subsequent activation of GP IIbIIIa receptor and stabilization of platelet aggregation. Currently available P2Y12 receptor inhibitors include ticlopidine, clopidogrel, prasugrel, and ticagrelor.
Ticlopidine was the first P2Y12 receptor inhibitor that was approved for use for secondary prevention of stroke and MI and for prevention of stent closure after percutaneous coronary intervention (PCI). Ticlopidine is a prodrug and requires biotransformation to active metabolite in liver. Its use can cause rare, but life-threatening side effects including thrombotic thrombocytopenic purpura or neutropenia; hence, its use has been replaced by other P2Y12 receptor inhibitors.
Clopidogrel is also a prodrug requiring hepatic metabolism to form active metabolite to irreversibly inhibit P2Y12 receptor. Extrapolation based on the CURE trial suggested that the combination of aspirin and clopidogrel appears to modestly reduce the combined incidence of cardiovascular death, MI, or stroke in USA/NSTEMI patients who are not undergoing revascularization procedures. However, this small additional benefit is at the expense of increased major or minor bleeding and cost.
The majority of clinical trials (CREDO, PCI-CURE, CLARITY, and COMMIT) testing the efficacy of aspirin and clopidogrel focus on high-risk acute coronary syndrome patients undergoing PCI. Based on these trials, current guidelines recommend treatment with aspirin and clopidogrel for 12 months for acute coronary syndrome patients undergoing PCI. The suggested loading and daily maintenance dose for clopidogrel are 300 mg and 75 mg, respectively. A higher loading dose (600 mg) and higher daily maintenance dose (150 mg) of clopidogrel for the first 7 days, using a dose of 75 mg/day thereafter, did not reduce the composite end point of cardiovascular death, MI, or stroke at 30 days when compared with the conventional dosing regimen but did result in a higher major bleeding rate, as demonstrated by the CURRENT-OASIS 7 trial. However in the subgroup of patients undergoing PCI, the high-dose clopidogrel approach reduced the risk of stent thrombosis and MI at the cost of excess bleeding risk.
Given that clopidogrel requires hepatic transformation into active metabolite, the gene polymorphism involving the key enzymes in the biotransformation has been detected, and such polymorphism may account for the variable platelet inhibition response in individual patients. It has been proposed that testing the degree of platelet inhibition after clopidogrel administration may identify patients with poor response to clopidogrel, and dosing of clopidogrel based on such results may improve clinical outcome. However, the results from the GRAVITAS trial failed to confirm this hypothesis. Hence, routine use of a platelet function test to dose clopidogrel in acute coronary syndrome patients is not recommended.
Prasugrel is a third-generation thienopyridine and a prodrug and, like clopidogrel, requires hepatic biotransformation to active metabolites. The biotransformation of prasugrel is more efficient compared to clopidogrel; hence, the onset of action is faster and the degree of platelet inhibition more potent.
The approved use of prasugrel is only for acute coronary syndrome patients undergoing PCI as tested in TRITON-TIMI 38 trial, with clinical benefit largely driven by reduction of non-fatal MI, not death or stroke, and at the expense of increasing life-threatening bleeding when compared to clopidogrel. The bleeding risk is increased in patients with history of stroke or transient ischemic attack, age greater than 75 years, or a body weight of less than 60 kg; hence, the use of prasugrel in these patient populations should be avoided. The recommended dose in current guidelines is a loading dose of prasugrel 60 mg given promptly or no later than 1 hour after PCI with 10 mg daily as maintenance dose for at least 12 months. The benefit of prasugrel in medically managed patients with USA/NSTEMI has not been established and is undergoing clinical testing.
Ticagrelor is a cyclopentyltriazolopyrimidine that directly and reversibly inhibits P2Y12 receptors on platelets. It has several unique pharmacologic features including fast absorption and short half-life with rapid onset and offset. Based on the PLATO trial, its use in acute coronary syndrome patients, regardless of treatment strategy (medical management, revascularization via PCI or coronary artery bypass graft [CABG]), was approved by U.S. Food and Drug Administration in July 2012 using a regimen with a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. This approval is accompanied with a warning stating that use of ticagrelor with aspirin with a dose greater than 100 mg/day decreases its effectiveness.
GP IIBIIIA Receptor Inhibitor
Activation of GP IIbIIIa receptors leads to interaction of receptors with ligands such as fibrinogen followed by platelet aggregation. Currently available intravenous GP IIbIIIa receptor inhibitors are abciximab, a monoclonal antibody against the receptor; nonpeptidic inhibitors, lamifiban and tirofiban; and a peptidic inhibitor, eptifibatide.
Four major randomized clinical trials (PRISM, PRISM-PLUS, PURSUIT, and PARAGON) evaluated the efficacy of intravenous GP IIbIIIa receptor inhibitors in reducing clinical events (death, MI, or refractory angina) in patients with USA/NSTEMI. Different inhibitors were tested in the trials (tirofiban in PRISM and PRISM-PLUS, eptifibatide in PURSUIT, and lamifiban in PARAGON). These trials differed in tested patient population, experimental designs, angiographic strategies, and end point measurement, but these trials showed consistent, although small, reductions in short-term composite event rates in the management of the acute phase of USA/NSTEMI when they were added to the background treatment of aspirin and heparin as a part of initial medical management. Meta-analysis of these trials indicated that patients with high-risk features would benefit more from the use of GP IIbIIIa inhibitors, especially when undergoing PCI.
The efficacy of intravenous abciximab on clinical outcome in patients with USA/NSTEMI without early intervention was tested in GUSTO-IV acute coronary syndrome trial. There was no survival benefit in patients receiving abciximab when compared with placebo at 30 days or at 1 year.
The efficacy of intravenous GP IIbIIIa inhibitors in reducing clinical events in patients with USA/NSTEMI undergoing PCI was also tested—abciximab in EPILOG and CAPTURE and tirofiban in RESTORE. These trials consistently showed a reduction of short-term clinical events (composite end point of death, MI, or urgent or repeat revascularization). The major benefit appears to be in nonfatal adverse events rather than mortality.
Thus, overall data suggest that intravenous GP IIbIIIa inhibitors used judiciously, along with aspirin and heparin, are beneficial in high-risk patients with USA/NSTEMI undergoing PCI.
In the modern era of frequent use of dual antiplatelet therapy (mostly aspirin and clopidogrel), routine addition of eptifibatide to aspirin and clopidogrel in managing USA/NSTEMI patients does not confer clinical benefit but increases bleeding risk as demonstrated by the EARLY-ACS trial. Current U.S. guidelines recommend use of GP IIbIIIa inhibitors as an alternative to clopidogrel as a second antiplatelet agent or in addition to clopidogrel as a third antiplatelet agent in high-risk patients undergoing initial invasive strategy. These agents are especially useful if invasive therapy is planned but must be delayed.
Unfractionated Heparin and Low-Molecular-Weight Heparin
The protective effect of intravenous unfractionated heparin (UFH) in treating unstable angina has been demonstrated in randomized trials. During short-term use, the risk of MI in unstable angina is reduced by about 90%, and ischemic episodes are reduced by about 70%. Current guidelines recommend intravenous administration of a bolus of 60–70 U/kg followed by 12–15 U/kg/h titrated to an activated partial thromboplastin time of 1.5 to 2 times normal for a duration of 2–5 days in patients with USA/NSTEMI.
Recently, low-molecular-weight heparin (LMWH) was tested to examine its role as an alternative anticoagulation therapy to UFH in patients with USA/NSTEMI. LMWH has certain pharmacologically superior features to UFH: longer half-life, weaker binding to plasma protein, higher bioavailability with subcutaneous injection, more predictable dose response, and less incidence of heparin-induced thrombocytopenia. Dalteparin has been shown to be superior to placebo and equivalent to UFH for immediate, short-term treatment of USA/NSTEMI in reducing composite end points in the FRISC and FRIC trials, respectively. In the FRISC II trial, dalteparin also lowered the risk of death or MI in patients receiving invasive procedures, especially in high-risk patients. In the ESSENCE and Thrombolysis in Myocardial Infarction (TIMI) 11B trials, enoxaparin (modestly but significantly) reduced the combined incidence of death, MI, or recurrent angina over UFH. This reduction is mainly due to a decrease in recurrent angina. But in the SYNERGY trial, enoxaparin was not superior to UFH in reducing mortality or nonfatal MI in high-risk patients undergoing early invasive therapy. Taken together, acute treatment with LMWH is likely as effective as UFH in USA/NSTEMI patients receiving aspirin. However, because LMWH is easier to use and does not require partial thromboplastin time monitoring, it is being increasingly preferred over UFH. Enoxaparin is the most studied LMWH, and its dose is 1 mg/kg subcutaneously twice daily with a treatment duration up to 8 days.
Direct Thrombin Inhibitors
Compared with heparin, direct thrombin inhibitors appear to offer a small reduction in death or MI in patients with USA/NSTEMI. Currently only bivalirudin is available for clinical use.
Bivalirudin was tested in the ACUITY trial in the setting of USA/NSTEMI. Bivalirudin was shown to be noninferior to heparin in composite ischemia end points (death, MI, or unplanned revascularization) in USA/NSTEMI patients with moderate- or high-risk features undergoing invasive therapy when it was used in conjunction with a GP IIbIIIa inhibitor. Taken together, direct thrombin inhibitors have not been routinely used in the medical management of USA/NSTEMI; however, they are alternative antithrombotics for patients with heparin-induced thrombocytopenia.
Fondaparinux is an indirect factor Xa inhibitor that works by reversible binding to antithrombin. When compared to enoxaparin in the OASIS-5 trial, fondaparinux was observed to have similar efficacy in reducing primary outcome of death, MI, or refractory ischemia with less major bleeding. However, catheter thrombus was noted to be more frequent than with enoxaparin, requiring additional bolus of UFH with empirically determined dose at the time of catheterization. Because of this disadvantage, fondaparinux is seldom used in USA/NSTEMI patients with planned early invasive approach. Fondaparinux is given at a dose of 2.5 mg/day subcutaneously and is contraindicated in patients with a creatinine clearance < 20 mL/min because its excretion is predominantly by kidneys.
Figure 7–1 summarizes the use of various antiplatelet, antithrombotic, and GP IIbIIIa inhibitors in different USA/NSTEMI settings.
Algorithm in risk stratification and management of unstable angina and non-ST elevation myocardial infarction (USA/NSTEMI). ASA, aspirin; CA, calcium; CABG, coronary artery bypass graft; CHF, congestive heart failure; CXR, chest x-ray; d/c, discontinue; ECG, electrocardiogram; GP, glycoprotein; GRACE, Global Registry of Acute Coronary Events; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.
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Endovascular interventions such as percutaneous coronary angioplasty and stenting are commonly performed in patients with unstable angina to reduce the critical stenosis in the culprit artery or in multiple coronary arteries. Although these interventions accomplish an acute reduction in the severity of stenosis in patients with unstable angina, they carry a somewhat higher risk of acute complications, including death (0–2%), abrupt closure (0–17%), acute MI (0–13%), and the need for urgent coronary artery bypass surgery (0–12%), than in patients with stable angina. The risk is especially great when the procedure is performed soon after the onset of symptoms, in the absence of prior treatment with heparin, or in the presence of an angiographically visible intracoronary thrombus. In the current era of stent placement for coronary intervention, the angiographic restenosis rate at 6- to 7-month follow-up with bare metal stents ranges from 22% to 32%, whereas it is less than 10% for drug-eluting stents even at longer follow-up, as demonstrated in clinical trials for uncomplicated lesions.
One of the important clinical decisions in treating USA/NSTEMI patients is whether to choose a “conservative” versus “invasive” approach based on patients' clinical risk profile. Patients demonstrating highest risk for short-term morbidity or mortality from USA/NSTEMI are those with refractory angina despite intensive antianginal treatment, severe heart failure or unstable hemodynamics, and life-threatening ventricular arrhythmias, and these patients should undergo immediate angiography with intention for revascularization within 2 hours of presentation. Patients without the aforementioned high-risk features but with elevated troponin level, dynamic ST-T changes on ECG, diabetes mellitus, renal insufficiency, left ventricular ejection fraction < 40%, early post-MI angina, PCI within 6 months, prior CABG, or intermediate to high GRACE score (> 140) should undergo invasive evaluation within 72 hours of admission. Other low-risk patients can undergo noninvasive evaluation for inducible ischemia before hospital discharge (conservative approach). If inducible ischemia is detected, patients should undergo coronary angiography.
Coronary Artery Bypass Surgery
Randomized trials and observational series have shown that surgical myocardial revascularization in patients with unstable angina is relatively superior to medical therapy for controlling symptoms and improving effort tolerance and ventricular function.
There is no clinical trial comparing PCI with CABG in patients with USA/NSTEMI. Surgical revascularization can be considered an appropriate option for patients with unstable angina who do not stabilize with aggressive medical therapy or for whom angioplasty is unsuccessful or is followed by acute complications not amenable to additional catheter-based intervention. It is also applicable to patients who have severe multivessel or left mainstem coronary artery disease, particularly when left ventricular function is also impaired. Although multivessel angioplasty is performed in many centers, the Bypass Angioplasty Revascularization Investigation (BARI) trial showed that CABG offered a lower repeat revascularization rate and a reduced incidence of clinical angina compared with multivessel percutaneous transluminal coronary angioplasty. The BARI trial also revealed that CABG has a better long-term survival benefit compared with multivessel percutaneous transluminal coronary angioplasty, especially in diabetic patients.
Intra-Aortic Balloon Counterpulsation
Intra-aortic balloon counterpulsation is a useful adjunct in managing selected cases of unstable angina. It helps maintain or improve coronary artery blood flow and myocardial perfusion by augmenting diastolic aortic pressure; at the same time, systolic unloading contributes to a reduction in ventricular wall tension and myocardial oxygen demand and an improvement in ventricular function. These beneficial effects on myocardial oxygen supply and demand help stabilize patients with recurrent myocardial ischemia and those with serious intermittent or persistent hemodynamic or electrical instability. Cardiac catheterization and revascularization can then be carried out with relative safety.
Intra-aortic balloon counterpulsation (and the percutaneous method of insertion) carries a significant risk of vascular complications involving the lower extremities, especially in women, in patients older than 70 years, and in the presence of diabetes or aortoiliac disease. It should be viewed as a temporary stabilizing measure, pending definitive revascularization.
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Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol.