TREATMENT Non-ST-Segment Elevation Acute Coronary Syndrome (Non-ST-Segment Elevation Myocardial Infarction and Unstable Angina) MEDICAL TREATMENT
Patients should be placed at bed rest with continuous ECG monitoring for ST-segment deviation and cardiac arrhythmias. Ambulation is permitted if the patient shows no recurrence of ischemia (symptoms or ECG changes) and does not develop an elevation of a biomarker of necrosis for 12–24 h. Medical therapy involves simultaneous anti-ischemic and antithrombotic treatments and consideration of coronary revascularization. ANTI-ISCHEMIC TREATMENT
To provide relief and prevention of recurrence of chest pain, initial treatment should include bed rest, nitrates, beta adrenergic blockers, and inhaled oxygen in the presence of hypoxemia (Table 40-1). Nitrates
These should first be given sublingually or by buccal spray (0.3–0.6 mg) if the patient is experiencing ischemic pain. If pain persists after three doses given 5 min apart, intravenous nitroglycerin (5–10 μg/min using nonabsorbing tubing) is recommended. The rate of the infusion may be increased by 10 μg/min every 3–5 min until symptoms are relieved, systolic arterial pressure falls to <100 mmHg, or the dose reaches 200 μg/min. Topical or oral nitrates (Chap. 39) can be used when the pain has resolved, or they may replace intravenous nitroglycerin when the patient has been pain-free for 12–24 h. The only absolute contraindications to the use of nitrates are hypotension or the use of sildenafil or other phosphodiesterase-5 inhibitors within the previous 24–48 h. Beta Adrenergic Blockers and Other Agents
Beta blockers are the other mainstay of anti-ischemic treatment. They may be started by the intravenous route in patients with severe ischemia, but this is contraindicated in the presence of heart failure. Ordinarily, oral beta blockade targeted to a heart rate of 50–60 beats/min is recommended. Heart rate–slowing calcium channel blockers, e.g., verapamil or diltiazem, are recommended for patients who have persistent symptoms or ECG signs of ischemia after treatment with full-dose nitrates and beta blockers and in patients with contraindications to either class of these agents. Additional medical therapy includes angiotensin-converting enzyme (ACE) inhibitors or, if these are not tolerated, angiotensin receptor blockers. Early administration of intensive HMG-CoA reductase inhibitors (statins), such as atorvastatin 80 mg/d, prior to percutaneous coronary intervention (PCI), and continued thereafter, has been shown to reduce complications of the procedure and recurrences of ACS. ANTITHROMBOTIC THERAPY
This is the second major cornerstone of treatment (Table 40-2). There are two components of antithrombotic therapy: antiplatelet drugs and anticoagulants. Antiplatelet Drugs
Initial treatment should begin with the platelet cyclooxygenase inhibitor aspirin. The typical initial dose is 325 mg/d, with lower doses (75–100 mg/d) recommended thereafter. Contraindications are active bleeding or aspirin intolerance. “Aspirin resistance” has been noted in 2–8% of patients but frequently has been related to noncompliance.
In the absence of a high risk for bleeding, patients with NSTE-ACS, irrespective of whether an invasive or conservative strategy (see below) is selected, should receive a platelet P2Y12 receptor blocker to inhibit platelet activation. The thienopyridine clopidogrel is an inactive prodrug that is converted into an active metabolite that causes irreversible blockade of the platelet P2Y12 receptor. When added to aspirin, so-called dual antiplatelet therapy, it has been shown to confer a 20% relative reduction in cardiovascular death, MI, or stroke, compared to aspirin alone, but to be associated with a moderate (absolute 1%) increase in major bleeding.
Continued benefit of treatment with the combination of aspirin and clopidogrel has been observed both in patients treated conservatively and in those who underwent PCI. This regimen should continue for at least 1 year in patients with NSTE-ACS, especially those with a drug-eluting stent, to prevent stent thrombosis. Up to one-third of patients have an inadequate response to clopidogrel, and a substantial proportion of these cases are related to a genetic variant of the cytochrome P450 system. A variant of the 2C19 gene leads to reduced conversion of clopidogrel into its active metabolite, which, in turn, reduces platelet inhibition and is associated with increases in the incidence of adverse cardiovascular events. Alternate P2Y12 blockers, such as prasugrel or ticagrelor (see below) used with aspirin, should be considered in patients with NSTE-ACS who develop a coronary event while receiving clopidogrel and aspirin or who are hyporesponsive to clopidogrel as identified by platelet and/or genetic testing, although such testing is not yet widespread.
A second P2Y12 blocker, prasugrel, also a thienopyridine, achieves a more rapid onset and higher level of platelet inhibition than clopidogrel. It has been approved for ACS patients following angiography in whom PCI is planned. It should be administered at a loading dose of 60 mg followed by 10 mg/d for up to 15 months. The TRITON-TIMI 38 trial showed that relative to clopidogrel, prasugrel reduced the risk of cardiovascular death, MI, or stroke significantly, albeit with an increase in major bleeding. Stent thrombosis was reduced by half. This agent is contraindicated in patients with prior stroke or transient ischemic attack or at high risk for bleeding. It has not been found to be effective in patients treated by a conservative strategy (see below).
Ticagrelor is a novel, potent, reversible platelet P2Y12 inhibitor. It has been shown in the PLATO trial to reduce the risk of cardiovascular death, MI, or stroke compared with clopidogrel in ACS patients who are treated by either an invasive or a conservative strategy. This agent reduced mortality but increased the risk of bleeding not associated with coronary artery bypass grafting. After a loading dose of 180 mg, 90 mg bid is administered as maintenance.
Prior to the development of the oral P2Y12 receptor blockers, many trials had shown the benefit of intravenous glycoprotein IIb/IIIa inhibitors. Their benefit, however, has been small (i.e., only a 10% reduction in death or MI, with a significant increase in major bleeding). Two recent studies failed to show a benefit of routine early initiation of a drug in this class compared with their use only in patients who undergo PCI. The addition of these agents to aspirin and a P2Y12 inhibitor (i.e., triple antiplatelet therapy) should be reserved for unstable patients with recurrent rest pain, elevated cTn, and ECG changes, as well as those who have a coronary thrombus evident on angiography when they undergo PCI. Anticoagulants
Four options are available for anticoagulant therapy to be added to antiplatelet agents: (1) unfractionated heparin (UFH), long the mainstay of therapy; (2) the low-molecular-weight heparin (LMWH), enoxaparin, which has been shown to be superior to UFH in reducing recurrent cardiac events, especially in patients managed by a conservative strategy but with some increase in bleeding; (3) bivalirudin, a direct thrombin inhibitor that is similar in efficacy to either UFH or LMWH but causes less bleeding and is used just prior to and/or during PCI; and (4) the indirect factor Xa inhibitor, fondaparinux, which is equivalent in efficacy to enoxaparin but appears to have a lower risk of major bleeding.
Excessive bleeding is the most important adverse effect of all antithrombotic agents, including both antiplatelet agents and anticoagulants. Therefore, attention must be directed to the doses of antithrombotic agents, accounting for body weight, creatinine clearance, and a previous history of excessive bleeding, as a means of reducing the risk of bleeding. Patients who have experienced a stroke are at higher risk of intracranial bleeding with potent antiplatelet agents and combinations of antithrombotic drugs. INVASIVE VERSUS CONSERVATIVE STRATEGY
Multiple clinical trials have demonstrated the benefit of an early invasive strategy in high-risk patients (i.e., patients with multiple clinical risk factors, ST-segment deviation, and/or positive biomarkers) (Table 40-3). In this strategy, following treatment with anti-ischemic and antithrombotic agents, coronary arteriography is carried out within ∼48 h of presentation, followed by coronary revascularization (PCI or coronary artery bypass grafting), depending on the coronary anatomy. In low-risk patients, the outcomes from an invasive strategy are similar to those obtained from a conservative strategy. The latter consists of anti-ischemic and antithrombotic therapy followed by “watchful waiting,” in which the patient is closely observed and coronary arteriography is carried out only if rest pain or ST-segment changes recur, a biomarker of necrosis becomes positive, or there is evidence of severe ischemia on a stress test.