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Melloni C, Jones WS, Washam JB, et al. Antiplatelet and Anticoagulant Treatments for Unstable Angina/Non–ST Elevation Myocardial Infarction [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Nov. (Comparative Effectiveness Reviews, No. 129.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Introduction

Background

Acute coronary syndrome (ACS) encompasses three similar yet distinct disorders: (1) ST-elevation myocardial infarction (STEMI), (2) non-ST elevation myocardial infarction (NSTEMI), and (3) unstable angina (UA). These disorders are often collapsed into just two categories—STEMI and UA/NSTEMI—because UA and NSTEMI have a similar pathophysiology, mortality rate, and management strategy when compared with STEMI. In the United States, approximately 1.4 million people are diagnosed with ACS each year, and 70 percent of them have UA/NSTEMI.1-4

UA/NSTEMI is defined by the presence of ischemic chest pain (or an equivalent), the notable absence of ST segment elevation on electrocardiography, and the presence of either ST segment depression or T-wave inversion on electrocardiography and/or abnormal cardiac biomarkers.1 The pathophysiology of UA/NSTEMI involves six possible etiologies: (1) thrombus arising from a disrupted or eroded plaque, (2) thromboembolism from an erosive plaque, (3) dynamic obstruction (such as coronary spasm), (4) progressive mechanical obstruction, (5) inflammation, or (6) coronary artery dissection.5 Most patients with UA/NSTEMI have thrombus formation or progressive arterial narrowing that leads to subtotal occlusion of an epicardial coronary artery.6 The difference between UA and NSTEMI is based on the presence of myocardial necrosis or infarction as suggested by serum tests such as creatine kinase-myocardial band, troponin I, or troponin T in NSTEMI.

Treatment Strategies for UA/NSTEMI

The standard treatment goals for patients with UA/NSTEMI involve the elimination of ischemic pain and the prevention of adverse events—death, recurrent ischemia, or myocardial infarction (MI). The cornerstone of short- and long-term treatment in all cases is medical therapy with antiplatelet and anticoagulant medications. Antiplatelet medications work by decreasing platelet aggregation and inhibiting thrombus formation. The timing of initiation of antiplatelet therapy in patients presenting with UA/NSTEMI is broadly classified as upstream if the therapy is initiated after admission but prior to cardiac catheterization or periprocedural if the agent is initiated at the time of or during the procedure. Antiplatelet therapy initiated during a hospitalization for UA/NSTEMI and continued for long-term management has been shown to reduce future cardiovascular events. Anticoagulant medications work by inhibiting blood clotting, either by antagonizing the effects of vitamin K or by blocking/inhibiting thrombin. The use of a parenteral anticoagulant, traditionally heparin, is standard treatment for patients hospitalized with ACS, and newer anticoagulants have been developed that improve outcomes, with similar or reduced bleeding risk compared with heparin.

By virtue of its ability to inhibit factors associated with thrombosis and to reduce ischemic outcomes, each antiplatelet or anticoagulant agent has the potential to increase the risk of bleeding. The tradeoff between reduced ischemic risk and increased bleeding risk has been highlighted in a number of recent large clinical trials that evaluated antiplatelet and anticoagulant therapies, as discussed below. Despite these recent data, a number of questions remain about the use of antiplatelet and anticoagulant agents, including the optimal dosing of certain agents and the timing of their use, and whether certain agents might be preferred for specific subgroups of patients.7

There are a number of challenges in determining optimal medical management in patients with UA/NSTEMI. First, there are a large number of agents in each category, increasing the complexity of assessing which combinations have the best outcomes. Second, optimal medical management may be affected by the choice of revascularization strategy. For the majority of patients who are at high risk of recurrent ischemia, MI, or death, an early invasive treatment strategy—defined as diagnostic angiography and coronary revascularization without prior noninvasive stress testing—has been proven to reduce death or MI.8-11 For the minority of patients at low or intermediate risk of recurrent ischemia, MI, or death, an initial conservative treatment strategy is often chosen: noninvasive stress testing followed by angiography and revascularization only in patients who develop recurrent infarction, angina at rest, or inducible ischemia during stress testing.1 Therefore, the comparative effectiveness of concurrent medical therapy needs to be considered separately for early invasive and initial conservative strategies. Finally, it is also important to consider the postdischarge treatment strategy (after hospitalization) using antiplatelet and/or anticoagulant treatments to reduce recurrent ischemic events.

Antiplatelet and Anticoagulant Medications for UA/NSTEMI

Table 1 outlines the antiplatelet and anticoagulant therapies available for each clinical scenario: early invasive, initial conservative, and postdischarge. These therapies are discussed below.

Table 1. Antiplatelet and anticoagulant therapies for each clinical scenario.

Table 1

Antiplatelet and anticoagulant therapies for each clinical scenario.

Aspirin and Antiplatelet Agents

In the absence of contraindications, aspirin is currently recommended for all patients presenting with ACS.1 Clopidogrel, the most widely used oral P2Y12 inhibitor, is currently recommended for patients with UA/NSTEMI. Other oral P2Y12 inhibitors include prasugrel and ticagrelor. While robust clinical data to support the use of clopidogrel in patients with ACS,12-14 several factors have been observed that make clopidogrel less than ideal. Clopidogrel belongs to the thienopyridine class of antiplatelet medications and is a prodrug that requires biotransformation to the active metabolite. This metabolic conversion takes place via the hepatic cytochrome P-450 isoenzymes and is susceptible to drug interactions and genetic polymorphisms that can potentially reduce the antiplatelet activity of the drug. Prasugrel is also a thienopyridine, but it provides a more potent and faster acting antiplatelet effect than clopidogrel and does not appear to be susceptible to genetic polymorphisms of the hepatic isoenzymes. Ticagrelor is a reversibly binding P2Y12 receptor antagonist that, when compared with clopidogrel, also provides a more rapid and more potent inhibition of platelets than clopidogrel does.15

The antiplatelet agents belonging to the glycoprotein IIb/IIIa inhibitor (GPI) class are administered intravenously. They include abciximab, eptifibatide, and tirofiban. Eptifibatide and tirofiban are reversible platelet inhibitors, whereas abciximab, a selective antibody, is an irreversible platelet inhibitor.

Anticoagulant Agents

Anticoagulants used to manage patients with UA/NSTEMI include unfractionated heparin (UFH), low molecular weight heparin (enoxaparin), bivalirudin, and fondaparinux. Intravenous UFH is the traditional anticoagulant used to manage UA/NSTEMI. Because of its short biologic half-life of approximately 1 hour, heparin must be given frequently or as a continuous infusion. Enoxaparin is a low molecular weight heparin that has the advantage of being administered subcutaneously once or twice daily and does not require frequent blood monitoring. Bivalirudin is a bivalent direct thrombin inhibitor that binds reversibly to thrombin. Bivalirudin possesses a favorable pharmacokinetic profile in that it is eliminated primarily by proteolytic cleavage, with approximately 20 percent being cleared by the kidneys, and has a plasma half-life of 25 minutes in patients with normal renal function. Fondaparinux is an indirect factor Xa inhibitor that is injected subcutaneously on a daily basis. Fondaparinux has been associated with a favorable bleeding profile when compared with other anticoagulants used in patients with ACS.

Treatment Strategy Algorithm

Figure 1 illustrates the treatment strategy algorithm for patients with UA/NSTEMI. First, all patients presenting with UA/NSTEMI are treated with an initial dose of aspirin, followed by either an early invasive or an initial conservative approach. An early invasive approach consists of an oral antiplatelet agent or intravenous (IV) GPI as initial therapy prior to going to the cardiac catheterization laboratory. After catheterization with percutaneous coronary intervention (PCI), the next stage involves consideration of the use of antiplatelet agents to improve cardiovascular outcomes. An initial conservative approach consists of using different anticoagulants and oral antiplatelets to improve cardiovascular outcomes in patients with UA/NSTEMI.

This figure illustrates the treatment strategy algorithm for patients with unstable angina/non-ST elevation myocardial infarction (UA/NSTEMI). First, all patients presenting with UA/NSTEMI are treated with an initial dose of aspirin, followed by either an early invasive or an initial conservative approach. An early invasive approach consists of an oral antiplatelet agent or intravenous GPI as initial therapy prior to going to the catheterization laboratory. After catheterization with percutaneous coronary intervention, the next stage considers the use of antiplatelet agents to improve cardiovascular outcomes. An initial conservative approach consists of using different anticoagulants and possibly adding oral antiplatelets to improve cardiovascular outcomes in patients with UA/NSTEMI. A subset of patients with recurrent ischemia or a positive noninvasive stress test will undergo cardiac catheterization with PCI. The last scenario for all patients with UA/NSTEMI is the postdischarge phase of treatment, which considers oral antiplatelet agents, aspirin for patients who are also receiving another oral antiplatelet agent, and the addition of proton pump inhibitors for reducing bleeding events in patients receiving dual antiplatelet therapy. The postdischarge strategy may include triple therapy (aspirin plus antiplatelet plus anticoagulant) for UA/NSTEMI patients with an indication for long-term anticoagulant therapy.

Figure 1

Treatment strategy algorithm for patients with UA/NSTEMI. GPI = glycoprotein IIb/IIIa inhibitor; KQ = Key Question; PCI = percutaneous coronary intervention; triple therapy = aspirin plus antiplatelet plus anticoagulant; UA/NSTEMI=unstable angina/non–ST (more...)

For all patients with UA/NSTEMI, the postdischarge phase of treatment considers oral antiplatelet agents, aspirin for patients who are also receiving another oral antiplatelet agent, and the addition of proton pump inhibitors for reducing bleeding events in patients receiving dual antiplatelet therapy. Last, the postdischarge strategy may include triple therapy (aspirin plus antiplatelet plus anticoagulant) for UA/NSTEMI patients with an indication (e.g., atrial fibrillation) for long-term anticoagulant therapy.

Although the treatment algorithm provides guidance to clinicians, there is still considerable uncertainty about the specifics of which medications to use in combination with other agents, the optimal dosing and timing of their use, and whether certain agents are more effective and safe in specific subgroups of patients. The treatment strategy usually consists of an anticoagulant with either an oral antiplatelet or IV GPI medication. Some trials assessed the combination and timing of using all three treatments (i.e., an anticoagulant, IV GPI, and an oral antiplatelet medication).

Scope and Key Questions

Scope of Review

This Comparative Effectiveness Review was funded by the Agency for Healthcare Research and Quality (AHRQ). The review was designed to evaluate the effectiveness and safety of antiplatelet and anticoagulant medications used to treat patients with UA/NSTEMI in an early invasive approach, an initial conservative approach, and after hospitalization (postdischarge).

Key Questions

With input from our Technical Expert Panel, we constructed Key Questions (KQs) using the general approach of specifying the population of interest, interventions, comparators, outcomes, timing of outcomes, and settings (PICOTS; see the section on “Inclusion and Exclusion Criteria” in the Methods section for details). The KQs considered in this Comparative Effectiveness Review were:

KQ 1. In patients undergoing an early invasive approach for treating unstable angina/non–ST elevation myocardial infarction (UA/NSTEMI):

  1. What are the comparative effectiveness (dose and timing) and comparative safety of an intravenous (IV) glycoprotein IIb/IIIa inhibitor versus oral antiplatelet agent as initial therapy before going to the catheterization laboratory?
  2. What are the comparative effectiveness (dose and timing) and comparative safety of coadministration of IV or oral antiplatelet agents in patients undergoing percutaneous coronary intervention for improving cardiovascular outcomes? Do the effectiveness and safety vary based on which initial anticoagulant is used or the combination of anticoagulant and antiplatelet agents?
  3. Based on demographic and other clinical characteristics, are there subgroups of patients for whom the effectiveness and safety differ?

KQ 2. In patients undergoing an initial conservative approach for treating UA/NSTEMI:

  1. What are the comparative effectiveness (dose and timing) and comparative safety of different anticoagulants for improving cardiovascular outcomes?
  2. What are the comparative effectiveness (dose and timing) and comparative safety of different antiplatelet agents for improving cardiovascular outcomes?
  3. Based on demographic and other characteristics, are there subgroups of patients for whom the effectiveness and safety differ?

KQ 3. In patients treated for UA/NSTEMI after hospitalization (postdischarge):

  1. What are the comparative effectiveness (dose and duration) and comparative safety of the available oral antiplatelet agents given in combination with aspirin? Do the effectiveness and safety vary based on the dose of aspirin used?
  2. What are the comparative effectiveness and comparative safety of proton pump inhibitors (PPIs) for reducing bleeding events in patients receiving dual antiplatelet therapy after UA/NSTEMI? Do the effectiveness and safety vary by oral antiplatelet therapy and PPI?
  3. In patients with an indication for long-term anticoagulant therapy, what are the comparative effectiveness and comparative safety of adding an oral anticoagulant to aspirin and another antiplatelet agent for improving cardiovascular outcomes?
  4. Based on demographic and other characteristics, are there subgroups of patients for whom the effectiveness and safety differ?

Analytic Framework

Figure 2 shows the analytic framework for this Comparative Effectiveness Review.

The analytic framework depicts the treatment strategies and outcomes for adult patients with UA/NSTEMI. In-hospital treatment interventions include an early invasive approach prior to catheterization or during percutaneous coronary intervention (Key Question 1) or an initial conservative approach (Key Question 2) involving the use of combinations of antiplatelets and/or anticoagulants to improve cardiovascular outcomes. Postdischarge treatment interventions (Key Question 3) involve the use of aspirin, oral antiplatelets, anticoagulants, and proton pump inhibitors to prevent recurrent ischemic events and other outcomes. Intermediate outcomes considered include rehospitalization, length of hospital stay, and resource utilization (e.g., emergency department visits). Final outcomes considered include all-cause death, cardiovascular-related death, nonfatal myocardial infarction, revascularization, stroke, and quality of life. The figure also considers whether there are subgroups of patients, based on demographic and other characteristics, for which the effectiveness and safety differ. All three Key Questions consider subgroups by age, sex, weight, body mass index, diabetes, heart failure, previous stroke, renal insufficiency, type of stent, type of vascular access. Finally, all three Key Questions consider safety risks including adverse drug reactions, bleeding, and stent thrombosis.

Figure 2

Analytic framework. KQ = Key Question; UA/NSTEMI = unstable angina/non–ST elevation myocardial infarction a Prior to catheterization or during percutaneous coronary intervention.

The analytic framework depicts the treatment strategies and outcomes for adult patients with UA/NSTEMI. In-hospital treatment interventions include an early invasive approach prior to catheterization or during percutaneous coronary intervention (KQ 1) or an initial conservative approach (KQ 2) involving the use of combinations of antiplatelets and/or anticoagulants to improve cardiovascular outcomes. Postdischarge treatment interventions (KQ 3) involve the use of aspirin, oral antiplatelets, anticoagulants, and proton pump inhibitors to prevent recurrent ischemic events and other outcomes.

Intermediate outcomes considered include rehospitalization, length of hospital stay, and resource utilization (e.g., emergency department visits). Final outcomes considered include all-cause death, cardiovascular-related death, nonfatal myocardial infarction, revascularization, stroke, and quality of life. The figure also includes consideration of whether there are subgroups of patients, based on demographic and other characteristics, for whom the effectiveness and safety differ. All three KQs consider subgroups by age, sex, weight, body mass index, diabetes, heart failure, previous stroke, renal insufficiency, type of stent, and type of vascular access. Finally, all three KQs consider safety risks including adverse drug reactions, bleeding, and stent thrombosis.

Cover of Antiplatelet and Anticoagulant Treatments for Unstable Angina/Non–ST Elevation Myocardial Infarction
Antiplatelet and Anticoagulant Treatments for Unstable Angina/Non–ST Elevation Myocardial Infarction [Internet].
Comparative Effectiveness Reviews, No. 129.
Melloni C, Jones WS, Washam JB, et al.

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