During episodes of ischemic chest pain, electrocardiogram (ECG) features may include (a) ST-segment elevation or depression, (b) T wave flattening or inversion, (c) premature ventricular contractions (PVCs), or (d) conduction disturbances, including bundle branch block (Fig. 21-1). Reversible ST depression or T wave inversion is seen in most patients if continuous ECG monitoring is used, a finding that may not emerge during a single 12-lead ECG. Even with intensive monitoring, ECG findings are absent in up to 15% of symptomatic patients with UA. Therefore, a normal ECG does not exclude a diagnosis of UA or MI. Conversely, up to 70% of all ECG-documented episodes of ischemia are clinically silent.

Elevated total CK (including the CK-MB fraction) and cardiac troponins (I and T) are markers of myocardial necrosis and indicate an MI, even in the absence of convincing ST segment-T wave changes. Troponins (I/T) are more sensitive and specific in making the diagnosis of an AMI than CK-MB. Troponin elevation in NSTE-ACS correlates with adverse prognosis. These are also patients who are likely to benefit from Glycoprotein 2b/3a (Gp2b/3a) receptor antagonist therapy and from early coronary angiography and revascularization. Highly sensitive C-reactive protein (hs-CRP) levels are also increased in patients with ACS. ACS patients with the highest levels of hs-CRP and troponins have the worst prognosis.

The principal measures to decrease myocardial oxygen consumption are to limit heart rate and afterload. These goals are immediately accomplished by curtailing physical activity with bedrest. Exercise stress-tests are contraindicated in unstable patients since frank infarction may ensue. Arrhythmias like atrial fibrillation (AF) and ST should be controlled, both to reduce O₂ consumption and to optimize diastolic filling time, thereby maximizing the sufficiency of coronary perfusion. Controlling hypertension and CHF decreases myocardial wall tension and therefore facilitates perfusion (see Chapter 22). Situations that increase heart rate (anxiety, use of short-acting nifedipine) or both heart rate and total body oxygen consumption (e.g., thyrotoxicosis, alcohol withdrawal, stimulant drug intoxication, anxiety, agitation, infections, etc.) should be promptly recognized and corrected. β-Blockers effectively reduce myocardial oxygen consumption by decreasing heart rate and cardiac contractility and improve O₂ supply by lengthening diastolic filling time. β-Blocking drugs are particularly useful in reducing oxygen consumption in the tachycardic and hypertensive patient with UA but are contraindicated in acute heart failure, coronary artery spasm, or severe bronchospasm. β-Blocking agents also reduce risk of tachyarrhythmias in patients with ACS.

The most important treatment under this category are the strategies for myocardial revascularization which include percutaneous coronary angioplasty, coronary stenting, and coronary artery bypass surgery (will be dealt with later in this chapter). Myocardial oxygen supply can also be increased simply by boosting hemoglobin saturation or elevating hemoglobin concentration to levels higher than 9 or 10 gm/dL, in severely anemic patients.

Pharmacotherapy is also necessary to optimize myocardial perfusion. Nitroglycerin (NTG) is used commonly and may be administered sublingually, orally, transcutaneously, or intravenously. (For unstable patients, the intravenous route is most reliable.) In addition to dilating coronary vessels, NTG also decreases wall tension of the LV by reducing preload and, to a lesser extent, afterload. Acting through these mechanisms, NTG also reduces the risks of life-threatening arrhythmias in acute ischemia. Nitrates are effective both for classical and variant angina because of their direct coronary vasodilating properties. NTG is titrated to relieve chest pain or to reduce blood pressure by 10% to 20%. Usually, intravenous doses of 0.7 to 2.0 μg/kg/min suffice. Intravenous NTG usually is begun at 5 to 15 μg/min and titrated upward as necessary in increments of 5 μg/min every 5 min up to a maximum dose of 200 μg/min. Headache is a common side effect but usually responds to simple oral analgesics. When the dose is excessive or the patient is dehydrated, hypotension and reflex tachycardia result from NTG-induced vasodilatation. These adverse effects usually can be offset by volume expansion or α-agonist therapy. Because ethanol is used as a vehicle for NTG infusions, violent adverse reactions may occur in patients taking Antabuse. Obviously, use of high doses of NTG for prolonged periods may also produce alcohol intoxication. Within 48 to 72 h of initiating NTG therapy, tolerance is often observed, necessitating higher
infusion rates. Rare problems induced by NTG therapy include increased intraocular and intracranial (IC) pressures and methemoglobinemia.

Coronary spasm, a major contributor to myocardial ischemia in certain settings, may be ameliorated by nitrates or calcium channel blockers. Blockers of slow calcium channels (e.g., nifedipine, nicardipine, and amlodipine) can be rapidly effective in reversing coronary spasm. In UA, these drugs should be viewed as adjuncts to nitrate, β-blocker, and antithrombotic therapy. Because calcium antagonists have vasodilating, negative inotropic, and positive chronotropic actions, they may have detrimental effects for certain patients. If coronary vasodilating effects predominate, the myocardial oxygen supply-demand balances benefits. Conversely, if systemic vasodilatation, hypotension, and reflex tachycardia predominate, myocardial oxygen demand can outstrip supply and ischemia can worsen. Therefore, caution must be exercised to avoid hypotension or excessive tachycardia when using calcium channel antagonists.

Most patients with NSTE-ACS have an ulcerated atherosclerotic plaque covered by a subocclusive accumulation of platelets, thrombin, and red blood cells. Typically, these patients have platelet-rich or “white-clot.” Therefore, aggressive antiplatelet therapies are effective in stabilizing patients with ACS. Aspirin (162 to 325 mg daily) should be initiated immediately for all patients with ACS unless compelling contraindications exist. Cyclooxygenase-1 (COX-1) mediated platelet aggregation is inhibited within 15 min of aspirin administration, if nonenteric coated tablets are chewed and swallowed. Aspirin reduces synthesis of both thromboxane A2 (TXA-2) as well as prostacyclin. TXA-2 is a powerful promoter of platelet aggregation. Prostacyclin, on the other hand, promotes vasodilatation and inhibits platelet aggregation. Low-dose aspirin preferentially inhibits TXA-2 synthesis, and endothelial prostacyclin synthesis is inhibited by high-dose aspirin. In the VA cooperative study, Canadian multicenter trial, and RISC trial, aspirin was found to reduce the risk of death and AMI by approximately 50% in patients with NSTE-ACS. In a large metaanalysis by the antithrombotic trialist collaboration, aspirin reduced risk of death, MI, and stroke by about 46%. The benefits of aspirin may persist for years with continued therapy. The risk of recurrent events is reduced by at least 25%. The risk of coronary reocclusion after PCIs is reduced by about 50% with use of aspirin. At the low doses (75 to 150 mg) needed for platelet inhibition, few hemorrhagic or gastrointestinal side effects occur. At a lower dose, aspirin caused 2.5% major bleeds with 1% requiring transfusions. Aspirin resistance is seen in about 5% to 10% of patients, and these individuals are at increased risk for cardiovascular events. Although inhibition of platelet aggregation may complicate subsequent coronary artery surgery, aspirin-related clotting defects are reversible with platelet transfusions. Dipyridamole does not enhance the protective effect of aspirin in coronary ischemia, but clopidogrel and ticlopidine do complement the anti-ischemic effect of aspirin.

These agents belong to the thienopyridine class. They prevent platelet aggregation by noncompetitive inhibition of the adenosine diphosphate (ADP) binding to the type 2 purinergic (P2Y₁₂) receptor, thereby inhibiting the activation of the glycoprotein IIb/IIIa receptor complex. Ticlopidine requires 3 to 6 days of therapy for full antiplatelet effect and carries a small risk of neutropenia (2.5%) and thrombotic thrombocytopenic purpura-hemolytic uremia syndrome (TTP-HUS). TTP-HUS occurs in the frequency of 1 in 1,500 to 5,000 patients taking ticlopidine. Both these life-threatening complications are most often seen within the first 12 weeks of therapy and necessitate immediate withdrawal of the drug. Patients with TTP-HUS may also need plasmapheresis. The usual dosage of ticlopidine is 250 mg by mouth twice daily. Ticlopidine has largely been replaced by clopidogrel.

Clopidogrel has been extensively studied in patients with ACS and in those who have received intracoronary stents. The life-threatening adverse effects seen with ticlopidine are far fewer with clopidogrel. In the CURE trial, clopidogrel use in ACS was found to significantly reduce risk of cardiovascular events (mostly reinfarctions) compared to aspirin alone. The usefulness of clopidogrel as an agent in reducing risk of cardiovascular events in patients who have received coronary stents has been clearly demonstrated in the PCI-CURE and CREDO trials. Clopidogrel is usually given as an oral bolus of 300 mg, followed thereafter at a dose of 75 mg once daily. Unlike ticlopidine, the antiplatelet effects of clopidogrel are seen within hours. Significant blood levels may be achieved sooner with a larger bolus dose of the medication (600 or 1,200 mg).
Along with ASA (81 mg once daily), it is given for a month after the implantation of bare-metal coronary stents and for at least 3 to 6 months after insertion of drug-eluting coronary stents. In patients with ACS, clopidogrel can be continued for 9 to 12 months. In some individuals at high risk for future cardiovascular events, clopidogrel with lowdose aspirin may be continued indefinitely if there are no contraindications and if cost is not an issue. There is a slight but significant increase in risk of bleeding with combination of clopidogrel and aspirin (3% to 5% risk of major bleeding), particularly in the elderly population.

Prasugrel is the latest of the oral thienopyridine ADP-receptor antagonists available for patients with ACS. It is more a powerful antiplatelet agent as compared with clopidogrel and ticlopidine.

The TRITON-TIMI 38 study compared combination of prasugrel and aspirin to combination of clopidogrel and aspirin in patients with ACS undergoing percutneous coronary intervention. There were over 13,000 patients in this study and the primary endpoint was reduction of cardiovascular death, nonfatal stroke and nonfatal MI over 6 to 15 month follow-up period. The major safety endpoint was major bleeding. There was a significant reduction in primary endpoints with prasugrel compared with clopidogrel, including significant reduction in death, target vessel revascularization, and stent thrombosis. The risk of stent thrombosis was reduced by nearly over 50%. However, there was a significant increase in risk of serious bleeding (both fatal and nonfatal), which somewhat offsets the benefits. This drug is not yet being routinely used, but is likely to become more popular as the role for drug-eluting stents (DES) begins to expand. This may be a good agent for those who present with stent thrombosis with clopidogrel, in those with multiple DES, and in those at less risk of bleeding (like younger patient population).

Gp2b/3a receptor inhibitor agents are the most powerful intravenous form of antiplatelet agents available. The Gp2b/3a receptor binds to fibrinogen, which actually forms the molecular link that bridges adjacent platelets in the process of platelet aggregation. By binding to the Gp2b/3a receptors, these agents inhibit binding of fibrinogen to this receptor and thus inhibit platelet aggregation. The use of these agents in the management of ACS has increased significantly in the last 8 to 10 years, with a positive impact on patient outcomes. There are two broad classes of these agents: (a) large-molecule agents like abciximab (ReoPro) and (b) small molecule agents (peptidelike eptifibatide [Integrilin] and non-peptide-like tirofiban [Aggrastat]). Because abciximab molecules bind irreversibly to the Gp2b/3a receptor and produce permanent noncompetitive platelet inhibition, the clinical effects of the medication can last for 7 to 10 days. Severe uncontrolled bleeding associated with abciximab should be addressed by stopping the medication and transfusing platelets. The small molecule agents bind reversibly to the Gp2b/3a receptor to produce competitive platelet inhibition. The antiplatelet effects usually reverse within 4 to 6 h of stopping the medication. Platelet transfusions should not be given for bleeding with small-molecule Gp2b/3a receptor antagonists, as their presence also inhibits new platelet formation.

There have been a number of studies that have proven the efficacy of these agents in reducing the risk of cardiovascular events (death, recurrent ischemia, MI) in patients with ACS. Their beneficial effects have also been proven in the setting of PCIs, both in the patients with ACS and in those with stable coronary artery disease undergoing elective PCI procedures. Typically, small-molecule agents like tirofiban or eptifibatide are used along with aspirin, heparin, and other usual medications for initial stabilization of patients with NSTE-ACS. Tirofiban and eptifibatide are given as a bolus, followed by infusion of the drug lasting for 24 to 72 h. These agents are most beneficial in reducing cardiovascular events of those ACS patients at greatest risk, like those with ST-T abnormalities on ECG, elevated troponins, diabetes mellitus, and those with higher TIMI risk scores. The maximum benefit from use of Gp2b/3a receptor antagonists is seen in those individuals who undergo PCI during their hospital stay. The agents are of questionable benefit in those at low risk (lower TIMI risk score) and those who do not undergo PCI. The majority of high-risk patients undergo coronary angiography and PCI while receiving these agents. The drug infusions are usually continued for 12 to 24 h after the coronary intervention. If patients need coronary bypass surgery, then the medication infusion is stopped for at least 4 to 6 h before proceeding with surgery to minimize risk of bleeding.

Abciximab, on the other hand, is the preferred Gp2b/3a receptor antagonist during PCI in patients with STEMI. However, most centers use the small-molecular weight agents even in patients with STEMI. Abciximab intravenous infusion is
continued for 12 h after PCI. If patients on abciximab need emergent bypass surgery, then the medication is stopped and the patients are given a 6- to 12-unit platelet transfusion before coming off the cardiopulmonary bypass pump.

The risk of major bleeding with Gp2b/3a receptor antagonists is 2.5% to 4.0%. Most of the bleeding experienced from these agents is from vascular access sites after PCI. Severe thrombocytopenia with counts less than 50,000/mm³ is seen in 0.5% to 1.5% of patients who receive abciximab. Because thrombocytopenia can develop within hours of initiating an abciximab infusion, it is prudent to check platelet counts within 4 h of starting the infusion and again at the end of the infusion. Severe thrombocytopenia is rare with small-molecule agents (tirofiban and eptifibatide). There is also a small chance (0.5% to 1.0%) of developing serious pulmonary hemorrhage with abciximab therapy. This is potentially fatal condition and is rarely if ever encountered with the small-molecular weight Gp2b/3a receptor antagonists. The reasons have made the small-molecular weight agents popular with the cardiologists.

Adequate doses of intravenous heparin given urgently along with oral aspirin reduce mortality and morbidity in patients with ACS severalfold by immediately interrupting the process of clotting on the coronary endothelium. The combination of heparin and aspirin is superior to aspirin alone in preventing the early complications of UA. Superiority of the combination probably results from the different mechanisms of the two treatments: heparin inhibits soluble clotting factors and thrombin-mediated platelet aggregation, whereas aspirin inhibits COX-mediated platelet aggregation. Even though the addition of heparin to aspirin raises the bleeding incidence slightly, the risk-benefit ratio almost always favors combination therapy. The goal of heparin therapy is to rapidly achieve and maintain a partial thromboplastin time (PTT) of 1.5 to 2.0 times the patient’s baseline or laboratory control value. This goal is best achieved using an intravenous bolus (60 units/kg, with a maximum dose of 4,000 units), followed by a continuous intravenous heparin infusion at a rate of 12 units/kg/h (maximum 1,000 units/h). The heparin infusion should be continued until coronary revascularization. Today, most of the ACS patients receive an intravenous infusion of a Gp2b/3a receptor antagonist for 12 to 24 h after PCI. They are also typically on aspirin and clopidogrel long term after PCI. In patients who are candidates for coronary bypass surgery, heparin and aspirin should be continued until surgery. In patients who are not candidates for coronary angiography and revascularization, heparin should be continued for 3 to 5 days. There is a risk of rebound angina when the heparin infusion is stopped. Thereafter, long-term use of aspirin alone can result in a 50% reduction in the incidence of angina recurrence.

Unfractionated heparin (UFH) is a heterogenous mixture of polysaccharides with molecular weights ranging from 3,000 to 30,000. There are several disadvantages with UFH. The antithrombin binding sites of heparin can be bound by a number of other plasma proteins, by platelet factor 4 and also by endothelial cells, thereby diminishing its therapeutic effect. Furthermore, heparin does not bind to clot-bound thrombin and to factor-Xa bound to platelets inside a clot. Thus, there is the possibility of clot propagation while the patient is receiving heparin. Heparin-induced thrombocytopenia (HIT) is another serious adverse effect.

These are homogenous glycosaminoglycans with molecular weight ranging from 4,000 to 6,000. Low-molecular-weight heparins (LMWH) have greater anti-factor Xa activity and less anti-factor IIa activity as compared to UFH. They act mainly by preventing thrombin generation and have lesser effect on a PTT as compared to UFH. Assays measuring anti-factor Xa activity are becoming available but are not yet in widespread use. Enoxaparin is the most popular of all LMWH that has been shown to be efficacious in patients with NSTE-ACS, as in acute pulmonary embolism and deep venous thrombosis. In the ESSENCE and TIMI 11B trials, enoxaparin has been demonstrated to have an advantage over intravenous heparin in reducing cardiovascular events in patients with NSTE-ACS. In a metaanalysis of these two trials, the risk of death, recurrent ischemia, and MI is reduced by about 20% by the use of enoxaparin as compared to UFH. In the ESSENCE trial, the benefit persisted for over a year. Similarly, dalteparin fared better than intravenous heparin in the FRISC trial in patients with ACS. The benefit was more pronounced in patients with high-risk features like troponin elevation and those with higher TIMI risk scores.

In patients with ACS who have creatinine clearance greater than 30 mL/min, enoxaparin is used in the dosage of 1 mg/kg subcutaneously twice daily. There is no need to monitor the clotting parameters because the therapeutic effect is quite consistent and predictable. The anticoagulant effect with enoxaparin is consistent because of very little binding to plasma proteins, endothelial cells, and macrophages. With newer assays being made available, one may soon be able to monitor anti-factor Xa activity when using enoxaparin. Enoxaparin’s risk of thrombocytopenia is quite low. Major bleeding is also uncommon with enoxaparin, but the risk may be higher in the elderly and those with renal failure. In patients requiring CABG, the drug should be stopped 12 to 24 h prior to the operation. In patients undergoing cardiac catheterization and PCI, there is always a concern for bleeding because of concomitant use of UFH, Gp2b/3a receptor antagonists, and clopidogrel. The following rule of thumb can be used for heparin dosing in patients needing PCI: within 8 h of having received a dose of enoxaparin, no additional UFH is needed for PCI; between 8 and 12 h, use UFH at dose of 25 to 50 units/kg; and if greater than 12 h after receiving enoxaparin, use 50 to 70 units/kg of UFH. Despite its proven efficacy, only about 15% of patients in North America and 50% of patients in Europe receive LMWH for ACS.

The direct thrombin inhibitor (DTI) agents available are hirudin, lepirudin (recombinant hirudin), argatroban, and bivalirudin. These agents are substantially more expensive than UFH and enoxaparin. They are powerful anticoagulants and their anticoagulation effect is consistent and predictable. DTIs do not depend on antithrombin III for their activity. They bind to thrombin (factor IIa) and thus inhibit coagulation process. Because thrombin is also a powerful platelet activator, DTIs also inhibit platelet activation. In a large metaanalysis, DTIs were shown to reduce rates of recurrent ischemia and infarctions as compared to heparin in patients with NSTE-ACS, but their use was associated with increased incidence of major bleeding requiring blood transfusions. DTIs are currently only recommended for those with HIT. However, the use of Bivalirudin in the setting of coronary intervention is increasing, ever since the REPLACE-2 trial showed significantly reduced procedure associated bleeding rates compared with heparin and Gp2b/3a receptor antagonists. This drug although expensive has become more popular with interventional cardiologists.