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Acute Coronary Syndromes
Acute coronary syndrome (ACS) leads to millions of hospital admissions worldwide each year and is a leading cause of death. Antithrombotic therapies are a cornerstone in the immediate and long-term management of ACS, reducing the risk of myocardial infarction (MI) and death in both medically and invasively managed patients. This chapter reviews fibrinolytic, antiplatelet, and anticoagulant therapies in the treatment of patients with ACS and provides a practical guide to several common hemostatic and thrombotic problems encountered in this patient population.
Classification
The clinical classification of ACS is based on the electrocardiogram (ECG) at the time of presentation and blood levels of cardiac biomarkers (troponin, creatine kinase). Patients with ST-segment elevation on the ECG and elevated cardiac biomarkers are diagnosed with ST-segment elevation MI (STEMI). Patients with non–ST-segment elevation (NSTE) ACS are subdivided according to whether or not they have elevated blood levels of cardiac biomarkers; those with elevated cardiac biomarkers are diagnosed with non–ST-segment elevation MI (NSTEMI), and those without elevated cardiac biomarkers are diagnosed with unstable angina.
Pathophysiology
Atherothrombosis plays a central role in the pathogenesis of ACS. Hypertension, dysglycemia, dyslipidemia, and toxins contained in tobacco cause endothelial injury. Lipid accumulation promotes an inflammatory response characterized by the recruitment of macrophages, smooth muscle cells, and fibroblasts to the site of injury and the formation of increasingly complex and unstable plaques with a necrotic core and fibrous cap. Disruption of the fibrous cap by shear forces and its degradation by enzymatic and cellular processes expose the plaque contents to the blood. Platelets adhere to exposed subendothelial proteins and become activated and aggregate. Exposed tissue factor induces thrombin generation on cellular surfaces, further promoting the formation of a platelet-fibrin thrombus that can occlude coronary blood flow. These processes are described in more detail in Chapter 142 .
The clinical manifestations of coronary atherothrombosis are influenced by the extent and duration of obstruction to blood flow and the presence or absence of collateral circulation. Patients with small plaques that do not significantly impair blood flow generally remain asymptomatic. Patients with significant flow-limiting plaques may develop ischemic symptoms (e.g., chest pain, breathlessness) during exertion when myocardial oxygen demand exceeds supply. Patients with acute plaque disruption with superimposed thrombus formation that completely obstructs coronary blood flow typically present with STEMI unless there is a robust collateral circulation. If obstruction to blood flow is transient or partial, patients typically present with NSTE ACS. If myocardial ischemia results in ventricular fibrillation, sudden cardiac death supervenes.
Antithrombotic Management
The goal of antithrombotic therapies in patients with ACS is to prevent new thrombus formation at the site of plaque disruption and facilitate lysis of intracoronary thrombus. Antithrombotic drugs are also used to prevent thrombus formation on the guide wires, catheters, and stents used to open occluded arteries and to prevent and treat left ventricular thrombus formation.
Although the pathophysiology is similar irrespective of whether patients present with STEMI or NSTE ACS, only STEMI patients benefit from immediate reperfusion therapy. This difference reflects the fact that most patients with NSTEMI do not have an occluded infarct-related coronary artery. Instead, they develop MI because of transient coronary artery occlusion or because of distal embolization of the thrombus.
Reperfusion Therapy For St-Segment Elevation Myocardial Infarction
Effective approaches to coronary reperfusion include mechanical (primary percutaneous coronary intervention [PCI]) and pharmacologic (fibrinolytic therapy) methods.
Primary Percutaneous Coronary Intervention
Primary PCI is preferred over fibrinolytic therapy in patients with STEMI because it produces higher patency rates and does not cause intracranial bleeding. Unlike fibrinolysis, which only treats the thrombus, primary PCI also allows treatment of the underlying atherosclerotic plaque. In high-income countries, most patients with STEMI are treated with primary PCI. In middle- and low-income countries, many centers lack the facilities and expertise to perform urgent coronary interventions, and only a minority of STEMI patients worldwide is treated with primary PCI. Patients undergoing primary PCI are routinely treated with antiplatelet and anticoagulant therapy (discussed in sections on Antiplatelet Therapy and Anticoagulant Therapy).
Fibrinolytic Therapy
Fibrinolytic drugs are plasminogen activators that initiate fibrinolysis by converting plasminogen to plasmin. Plasmin degrades fibrin resulting in clot lysis and recanalization of thrombotic occlusion. Restoration of coronary blood flow limits infarct size and improves myocardial function and survival.
The pharmacologic characteristics of the fibrinolytic drugs most used in the management of ACS are summarized in Table 145.1 . Streptokinase was the first agent to be evaluated in large-scale randomized controlled trials. A non–fibrin-specific agent, streptokinase, indirectly activates plasminogen, whereas the more fibrin-specific agents alteplase, reteplase, and tenecteplase directly convert plasminogen to plasmin. Reteplase and tenecteplase have longer half-lives than alteplase, enabling them to be given by double- or single-bolus injection, respectively, which simplifies administration. The direct-acting fibrinolytic agents are more fibrin specific than streptokinase because they bind to fibrin, where they convert fibrin-bound plasminogen to plasmin. Consequently, these agents produce a less marked systemic lytic state than streptokinase, which has no fibrin affinity. Avoidance of a systemic lytic state, which is characterized by a reduction in the circulating level of fibrinogen, is an important potential advantage of fibrin-specific drugs because this can be expected to be associated with a lower risk of bleeding complications.
Table 145.1
Pharmacologic Characteristics of Fibrinolytic Drugs Used in the Management of Patients With ST-Segment Elevation Myocardial Infarction
| Characteristic | Streptokinase | Alteplase | Reteplase | Tenecteplase |
|---|---|---|---|---|
| Fibrin specificity a | – | ++ | + | +++ |
| Dose | 1.5 million units | 100 mg | 20 U | 30–50 mg |
| Administration | Infusion over 30–60 min | Bolus 15 mg; then infusion 0.75 mg/kg (maximum, 50 mg) over 30 min, 0.5 mg/kg (maximum, 35 mg) over the next 60 min | Double bolus, 10 U over 2 min; then repeat 10 U bolus after 30 min | Single weight-adjusted bolus, <60 kg = 30 mg, 60–69 kg = 35 mg, 70–79 kg = 40 mg, 80–89 kg = 45 mg, ≥90 kg = 50 mg |
| Half-life (min) | 18–23 | 3–4 | 18 | 20 |
| Adjunctive antiplatelet therapy b | Aspirin | Aspirin | Aspirin | Aspirin |
| Adjunctive anticoagulant therapy | Heparin in patients at high risk of thromboembolism c | Heparin 60 U/kg bolus (maximum, 4000 U); 12 U/kg/h (maximum, 1000 U/h) | Heparin 60 U/kg bolus (maximum, 4000 U); 12 U/kg/h (maximum, 1000 U/h) | Heparin 60 U/kg bolus (maximum, 4000 U); 12 U/kg/h (maximum, 1000 U/h) |
a Less fibrin specificity is associated with more systemic fibrinogen depletion.
b Fibrinolytic drugs were evaluated on a background of aspirin, but the addition of clopidogrel to aspirin was subsequently shown to provide incremental benefit.
c High-risk patients include those with large or anterior myocardial infarction, atrial fibrillation, known left ventricular thrombus, or previous thromboembolism.
Initial trials with streptokinase established the efficacy of fibrinolytic therapy for reduction in the risk of MI and death; subsequent trials compared the efficacy and safety of newer fibrinolytic drugs with those of streptokinase or alteplase.
Streptokinase
Streptokinase is a single-chain polypeptide derived from β-hemolytic Streptococcus cultures. After intravenous (IV) administration, streptokinase binds to plasminogen, and the resulting streptokinase–plasminogen enzymatic complex converts plasminogen to plasmin. Because plasmin nonspecifically degrades circulating fibrinogen as well as fibrin, streptokinase produces a systemic lytic state. Streptokinase induces the formation of anti-streptokinase antibodies and can cause allergic reactions, particularly with repeated administration. Severe reactions are rare, but rash, shivering, pyrexia, and mild hypotension occur in up to 10% of patients. It is uncertain whether neutralizing antibodies reduce the efficacy of streptokinase.
The GISSI-1 (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico 1) trial, which was conducted in 11,806 patients with STEMI, demonstrated that compared with no lytic therapy, streptokinase (1.5 million units over 1 hour) significantly reduced 21-day in-hospital mortality (10.7% vs. 13.0%; P = .0002). A similar reduction in mortality was seen when the same dose of streptokinase was compared with no lytic therapy in 17,187 patients with suspected MI in the ISIS-2 (International Studies of Infarct Survival 2) trial (9.2% vs. 12.0%; P < .00001).
Alteplase
Alteplase is a recombinant tissue-type plasminogen activator that directly converts plasminogen to plasmin. Although more fibrin-specific than streptokinase, alteplase still induces a systemic lytic state. It has a short circulating half-life of 3 to 4 minutes, which necessitates its administration by a bolus followed by a continuous IV infusion.
The ISIS-3 ( n = 41,299) and GISSI-2 ( n = 20,891) trials found no benefit of alteplase over streptokinase; findings possibly explained by the suboptimal use of heparin in conjunction with a short-acting fibrinolytic agent (heparin was given subcutaneously after a delay of 4 to 12 hours) and lack of front-loading of alteplase. The GUSTO-1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator to Treat Occluded Arteries 1) trial ( n = 41,021) demonstrated that front-loaded alteplase (15 mg bolus, followed by 0.75 mg/kg [maximum, 50 mg] as an infusion over 30 minutes and then 0.50 mg/kg [maximum, 35 mg] over 60 minutes [maximum, 100 mg over 90 minutes]) plus IV heparin (5000 U IV bolus, followed by 1000 U/hour as an infusion, with the dose titrated to achieve an activated partial thromboplastin time [aPTT] of 60 to 85 seconds) compared with streptokinase (1.5 million units over 1 hour) with or without IV heparin, reduced 30-day mortality (6.3% vs. 7.3%; P = .001). The mortality benefits of alteplase were greatest in patients younger than the age of 75 years and those with anterior MI. Despite its enhanced fibrin specificity, alteplase was not associated with less bleeding than streptokinase.
The greatest benefits of fibrinolytic therapy are seen in patients treated within 1 hour of symptom onset; there is a much smaller benefit or no benefit if treatment is commenced more than 6 hours after symptom onset.
Reteplase
Reteplase is a second-generation non-glycosylated deletion mutant of alteplase. Reteplase is less fibrin-specific than alteplase but has a longer half-life (18 minutes) that enables administration by double-bolus IV injection.
The INJECT trial ( n = 6010) demonstrated that reteplase and streptokinase were associated with similar 35-day rates of mortality (9.0% vs. 9.5%), in-hospital stroke (1.2% vs. 1.0%), and major bleeding (0.7% vs. 1.0%), although reteplase was associated with a twofold higher rate of intracranial bleeding (0.8% vs. 0.4%). The GUSTO-III trial ( n = 15,059) demonstrated that reteplase (two 10-mg IV bolus injections given 30 minutes apart) and front-loaded alteplase were associated with similar 30-day rates of mortality (7.5% vs. 7.2%) and stroke (1.6% vs. 1.7%).
Tenecteplase
Tenecteplase is a third-generation multiple point mutant of alteplase. Tenecteplase has a half-life of 20 minutes and is given by a single bolus injection. Tenecteplase is the most fibrin-specific fibrinolytic drug approved for clinical use.
The ASSENT-2 (Assessment of the Safety and Efficacy of a New Thrombolytic) study, which enrolled 16,949 STEMI patients, showed that tenecteplase and alteplase were associated with similar 30-day rates of mortality (6.2% vs. 6.2%) and stroke (1.8% vs. 1.7%). Tenecteplase did not reduce the risk of intracerebral bleeding compared with alteplase (1% vs. 1%) but reduced the rate of major noncerebral bleeding (4.7% vs. 5.9%; P < .0002), possibly reflecting its enhanced fibrin specificity.
Adjunctive Antithrombotic Therapy in Patients Receiving Fibrinolytic Drugs
A compelling rationale exists to administer adjunctive antithrombotic therapy to STEMI patients treated with fibrinolytic therapy. Platelet-rich thrombi that form after plaque rupture are relatively resistant to degradation, and the use of concomitant antiplatelet and anticoagulant therapy may help to promote clot lysis. Fibrinolytic drugs have an early activating effect on platelets, and the plaque rupture site remains prothrombotic after successful reperfusion therapy. Evidence in support of the efficacy of adjuvant antiplatelet and anticoagulant therapy in patients with STEMI is summarized in the sections on antiplatelet and anticoagulant therapy, respectively.
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