Acute non-ST-elevation acute coronary syndromes: Initial antiplatelet therapy

INTRODUCTION — In patients with acute coronary syndromes (ACS), antiplatelet therapy inhibits platelet-mediated thrombosis and reduces the clinical risk of death and recurrent myocardial infarction (MI).

This topic addresses the use of antiplatelet therapy in patients with acute non-ST-elevation acute coronary syndromes (NSTEACS) based on the strategy chosen for management (ie, invasive strategy, noninvasive strategy) (algorithm 1) and covers the initial approach to the type and timing of antiplatelet therapy in patients with NSTEACS.

Other relevant topics include:

●(See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization".)

●(See "Anticoagulant therapy in non-ST-elevation acute coronary syndromes".)

●(See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

EMPIRIC ANTIPLATELET THERAPY

Initial therapy (dual antiplatelet therapy) — In patients with NSTEACS, we recommend treatment with aspirin plus a P2Y₁₂ inhibitor (eg, ticagrelor, prasugrel) rather than aspirin alone. Aspirin should be administered rapidly (eg, within 10 minutes of presentation) in patients suspected of acute MI. (See 'Aspirin' below.)

The timing of P2Y₁₂ inhibitor administration and choice of agent depends on the strategy chosen to manage NSTEACS (algorithm 1). (See 'Invasive strategy' below and 'Noninvasive strategy' below.)

This approach is consistent with North American and European guidelines [1,2].

Aspirin reduces the risk of mortality in patients with myocardial infarction. The efficacy of aspirin in patients with ACS was established in the ISIS-2 trial, in which treatment with aspirin reduced the five-week rate of cardiovascular mortality compared with placebo (9.4 versus 12 percent; p<0.00001) [3]. The risk of bleeding was similar between groups (0.4 percent).

Compared with aspirin alone, aspirin plus a P2Y₁₂ inhibitor reduces the risk of recurrent MI in patients with NSTEACS treated with or without percutaneous coronary intervention (PCI). In the CURE trial, 12,562 patients who presented within 24 hours after the onset of an NSTEACS were randomly assigned to receive either aspirin alone (75 to 325 mg/day) or aspirin plus clopidogrel (300 mg loading dose immediately followed by 75 mg/day) [4]. The majority of patients had features of non-ST-elevation MI (NSTEMI; eg, ST changes, elevated cardiac enzymes). Over 60 percent of patients enrolled did not undergo revascularization. At an average follow-up of nine months, patients assigned to aspirin plus clopidogrel had a lower rate of MI (5.2 versus 6.7 percent; relative risk [RR] 0.77, 95% CI 0.67-0.89) and a similar rate of cardiovascular death (5.1 versus 5.5 percent; RR 0.93, 95% CI 0.79-1.08) compared with aspirin alone. The effect of clopidogrel therapy was similar regardless of revascularization status and was similar across the spectrum of risk as calculated by the Thrombolysis In Myocardial Infarction risk score (calculator 1) [5,6].

Invasive strategy — For the management of patients who will undergo an invasive strategy, the timing and choice of antiplatelet therapy are as follows:

Timing of therapy — For patients with NSTEACS who will undergo an invasive strategy (algorithm 1), we suggest treatment with a P2Y₁₂ inhibitor after coronary angiography and prior to PCI rather than prior to coronary angiography. In patients who are likely to have a delay of at least 24 hours from the time of diagnosis until coronary angiography, it is reasonable to begin P2Y₁₂ inhibitor therapy at the time of diagnosis.

In patients who undergo angiography but do not undergo PCI, the approach to antiplatelet therapy depends on the next steps in management. Patients managed medically should receive antiplatelet therapy similar to patients managed with a noninvasive strategy, while patients who will undergo coronary artery bypass graft surgery (CABG) typically receive an individualized approach to antiplatelet therapy based on the timing of surgery. The approaches to these groups of patients are discussed elsewhere in this topic. (See 'Noninvasive strategy' below and 'Therapy prior to CABG' below.)

These approaches are consistent with North American and European guidelines [1,2].

The evidence suggests no clear advantage in terms of mortality or recurrent MI with P2Y₁₂ inhibitor administration prior to angiography and a possible increase in the risk of significant bleeding. In addition, our experience is that pretreatment with a P2Y₁₂ before knowing the coronary anatomy can delay surgery in patients who are referred for CABG, which is the approach to revascularization in 2 to 6 percent of patients with NSTEACS [7-11]. The evidence on timing of therapy includes:

●In a meta-analysis that included 13,226 patients with NSTEACS, pretreatment and no pretreatment with a P2Y12 inhibitor had similar rates of death (<1 percent in both groups; odds ratio [OR] 0.79, 95% CI 0.49-1.3) and recurrent MI (4.4 versus 4.7 percent; OR 0.9, 95% CI 0.68-1.2), but the rate of major bleeding was higher in patients who received pretreatment (5 versus 3 percent; OR 1.5, 95% CI 1.2-2.0) [7].

●The DUBIUS trial randomly assigned 1449 patients with NSTEACS managed with an invasive strategy to ticagrelor or no P2Y₁₂ inhibitor before angiography [11]. The median time to angiography was 23.3 hours. The rate of the primary composite endpoint was similar between the two groups. The trial was stopped early for futility.

●In the ACCOAST trial, 4033 patients with NSTEMI who were scheduled to undergo invasive management within 2 to 48 hours were randomly assigned to prasugrel 30 mg before angiography or to placebo [10]. At seven days, the rate of the primary composite efficacy endpoint was similar in the two groups (10.0 versus 9.9 percent). However, the rate of bleeding was higher in patients assigned to pretreatment with prasugrel (2.6 versus 1.4 percent; hazard ratio [HR] 1.90, 95% CI 1.19-3.02). The results were similar in the subgroup of patients underwent PCI, and the mean time to PCI was 4.4 hours after study drug administration [8].

Choice of agent — The choice of agent depends on the timing of therapy:

●P2Y₁₂ therapy prior to PCI – In patients who will be managed with an invasive strategy that includes dual antiplatelet therapy (DAPT; aspirin plus a P2Y₁₂ inhibitor) after angiography and prior to PCI, we recommend prasugrel or ticagrelor rather than clopidogrel.

This approach is consistent with European guidelines, while North American guidelines are less certain on the preference of ticagrelor or prasugrel over clopidogrel [1,2].

The evidence suggests that ticagrelor reduces the risk of mortality and recurrent MI compared with clopidogrel, while prasugrel only decreases the risk of recurrent MI compared with clopidogrel. The relative efficacy of prasugrel and ticagrelor is not clearly defined; the only study that directly compared these agents administered the agents at different points in the clinical course (ie, prior to angiography for ticagrelor, after angiography for prasugrel).

•In the ISAR-REACT 5 trial, 4018 patients with ACS (59 percent NSTEACS) and invasive management were randomly assigned to a strategy of pretreatment with ticagrelor or to postangiography treatment with prasugrel [12,13]. The rate of MI was higher in the ticagrelor pretreatment group compared with the prasugrel posttreatment group (4.8 versus 3 percent; HR 1.63, 95% CI 1.2-2.3), while the rate of death was not clearly different between groups (4.5 versus 3.7 percent, HR 1.23, 95% CI 0.9-1.7).

•The TRITON-TIMI 38 trial compared prasugrel with clopidogrel in 13,608 moderate- to high-risk ACS patients undergoing PCI, including 10,074 with NSTEACS [14]. In the majority of cases, both clopidogrel and prasugrel were given after coronary angiography but before PCI. At 15-month follow-up, the rate of nonfatal MI was lower with prasugrel compared with clopidogrel (7.3 versus 9.5 percent; HR 0.76, 95% CI 0.67-0.85), while the rate of mortality was similar (2.1 versus 2.4 percent). An exploratory analysis suggested that patients with prior stroke or transient ischemic attack who were treated with prasugrel had a higher rate of net harm (death, recurrent MI, stroke, or major bleeding) than did patients treated with clopidogrel (HR 1.5, 95% CI 1.02-2.3).

•In the PLATO trial, 18,624 patients with ACS (43 percent of whom had NSTEMI) were randomly assigned to ticagrelor or clopidogrel [15]. Approximately 46 percent of patients in both groups received clopidogrel prior to randomization, and the median time from the first dose of the study drug to PCI was approximately four hours (interquartile range [approximately] 0.5 to 50 hours). Ultimately, patients were managed with PCI (64 percent), CABG (10 percent), or medical therapy alone. At 12 months, the rates of mortality (4 versus 5.1 percent; HR 0.79, 95% CI 0.75-0.91) and recurrent MI (5.8 versus 6.9 percent; HR 0.84, 95% CI 0.75-0.95) were lower in the ticagrelor group compared with the clopidogrel group.

●P2Y₁₂ therapy prior to coronary angiography – In patients who will receive DAPT prior to planned coronary angiography, we recommend ticagrelor rather than clopidogrel. Prasugrel is typically not used for pretreatment due to a higher rate of bleeding.

Indirect data suggest greater efficacy with ticagrelor compared with clopidogrel and a higher rate of bleeding in patients assigned to prasugrel compared with clopidogrel [8,15]. In the PLATO trial, the rates of death and recurrent MI were lower in patients assigned to ticagrelor compared with those assigned to clopidogrel [15]. In the ACCOAST trial, pretreatment with prasugrel and clopidogrel had similar rates of death and recurrent MI, but the group assigned to prasugrel had a higher rate of bleeding [8].

Noninvasive strategy — For patients managed with a noninvasive strategy (algorithm 1) and DAPT, we suggest ticagrelor rather than clopidogrel. In patients who cannot take ticagrelor, treatment with clopidogrel is a reasonable option. Prasugrel is typically not used for noninvasive management due to a higher rate of bleeding. Therapy with DAPT should begin as soon as the decision is made to pursue a noninvasive strategy.

This approach is consistent with North American and European guidelines [1,2].

In patients managed with a noninvasive strategy, DAPT with ticagrelor likely reduces the risk of recurrent MI compared with other P2Y₁₂ inhibitors. Compared with clopidogrel, patients treated with prasugrel had similar rates of mortality or recurrent MI and a possible increase in the risk of bleeding:

●In the PLATO trial, the incidence of death (4.5 versus 5.9 percent; HR 0.78, 95% CI 0.69-0.89) and MI (5.8 versus 6.9; HR 0.84, 95% CI 0.75-0.95) were lower with ticagrelor than with clopidogrel [15]. The benefit of ticagrelor was similar in the group of patients managed without PCI (noninvasive strategy) compared with those managed with PCI (ie, invasive versus noninvasive strategy) [16].

●The TRILOGY ACS trial directly compared prasugrel with clopidogrel in 9326 patients with NSTEACS and in whom PCI was not performed [17]. Prasugrel was given with a loading dose of 30 mg and a maintenance dose of 10 mg daily in patients less than 75 years old or 5 mg daily for those 75 years or older or who weighed less than 60 kg. The rates of cardiovascular death and MI were similar in both groups. There was a higher rate of major bleeding in patients assigned to prasugrel (2.4 versus 1.8 percent; HR 1.3, 95% CI 1.0-1.7).

SPECIAL CIRCUMSTANCES

Older patients and low body weight — Most patients ≥75 years of age and those with body weight ≥60 kg can be treated with the usual regimen and dose of antiplatelet therapy (eg, aspirin plus a P2Y₁₂ inhibitor), but in patients ≥75 years of age or who weigh less than 60 kg and who will be treated with prasugrel, we use a lower maintenance dose (eg, 5 mg rather than 10 mg daily). (See 'Prasugrel' below.)

In general, increasing age is associated with higher risks of both bleeding and recurrent ischemic events. However, trials have not clearly identified differences between agents or the ideal approach to dosing of P2Y₁₂ inhibitors in older patients. Based on the presence of higher concentrations of the active metabolite of prasugrel in older patients and in those with lower body weight, patients in the TRILOGY trial were treated with a lower dose of prasugrel [18]. With this dose reduction in place, older patients and patients with lower body weight had a similar rate of death, MI, and bleeding events compared with patients randomly assigned to clopidogrel [17,19]. In the POPular AGE trial, 1002 patients with NSTEACS ≥70 years of age were randomly assigned to clopidogrel or ticagrelor therapy for one year [20]. A small number of the patients (5 percent of the "ticagrelor group") were assigned to receive prasugrel. Approximately 65 percent of patients underwent coronary artery revascularization. The rate of mortality (7 percent) and recurrent MI (8 percent) was similar in patients assigned to clopidogrel or ticagrelor, while the rate of minor and major bleeding was likely lower with clopidogrel.

Cerebrovascular disease — In patients with cerebrovascular disease, prasugrel should be avoided based on exploratory analysis from the TRITON-TIMI 38 trial, which is described elsewhere in this topic [14]. (See 'Choice of agent' above.)

Patients taking oral anticoagulants — In the acute management of ACS in patients with long-term needs for anticoagulation (eg, mechanical valve, atrial fibrillation), the initial approach to antiplatelet therapy includes dual antiplatelet therapy as indicated for the management strategy of choice. (See 'Invasive strategy' above and 'Noninvasive strategy' above.)

After acute management concludes (eg, stenting, normal stress testing), a decision on the intensity of antithrombotic therapy must be made. The approach to long-term therapy with oral anticoagulation plus a P2Y₁₂ inhibitor with or without aspirin is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients", section on 'Rivaroxaban'.)

Therapy prior to CABG — P2Y₁₂ inhibitors should be discontinued prior to coronary artery bypass graft surgery (CABG) to reduce the risk of operative bleeding. For patients treated with prasugrel, we stop therapy at least seven days prior to surgery. For patients treated with ticagrelor or clopidogrel, we stop therapy at least five days before surgery.

In patients receiving a glycoprotein (GP) IIb/IIIa inhibitor, it should be discontinued at least two to four hours before surgery [21].

The use of a P2Y₁₂ inhibitor prior to surgery is associated with more severe bleeding, and there is no clear evidence that treatment with a P2Y₁₂ inhibitor prior to CABG reduces the risk of important outcomes:

●A 2011 systematic review and meta-analysis evaluated outcomes from over 10 heterogenous studies that included ACS patients who underwent CABG on or off clopidogrel [22]. In those with clopidogrel exposure within five days of CABG, the rates of death, stroke, and the combined rate of death, stroke, and MI were nonsignificantly higher (odds ratio [OR] 1.44, 95% CI 0.97-2.13; 1.23, 95% CI 0.66-2.29; and 1.10, 95% CI 0.87-1.41, respectively).

●Among 2072 patients who underwent CABG in the CURE trial, the likelihood of CURE-defined major bleeding within seven days of CABG was nonsignificantly increased in patients who received clopidogrel within the five days prior to CABG (9.6 versus 6.3 percent with placebo) but not in those who had discontinued clopidogrel ≥5 days prior to CABG (4.4 versus 5.3 percent) [23]. In another subgroup analyses of patients undergoing CABG in the CURE trial, patients with ACS who received clopidogrel had a lower rate of adverse outcomes than those who did not. This finding is supported by several observational studies [24-28]. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Bleeding'.)

High-risk scenarios — There is a limited role for additional antiplatelet therapy (eg, GP IIb/IIIa inhibitor) in patients with NSTEACS. We avoid use of GP IIb/IIIa inhibitors prior to angiography or percutaneous coronary intervention (PCI). Scenarios in which a GP IIb/IIIa inhibitor may be beneficial include:

●Ongoing ischemia despite dual antiplatelet therapy – Patients who received aspirin and a P2Y₁₂ inhibitor but who have evidence of ongoing ischemia (eg, persistent chest pain and electrocardiographic evidence of ischemia) may benefit from addition of a GP IIb/IIIa inhibitor. However, in such cases, urgent angiography is the usual approach to management (algorithm 1). (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization", section on 'Signs of ongoing myocardial dysfunction or infarction'.)

●High-risk characteristics identified during angiography – Patients who have high-risk features during angiography, such as large thrombus burden or an intraprocedural thrombotic complication (eg, coronary dissection), may benefit from additional antiplatelet therapy.

●Select patients with multivessel disease – In rare cases in which CABG surgery is planned after recent (eg, <30 days) stent placement, administration of a GP IIb/IIIa inhibitor may be substituted for a P2Y₁₂ inhibitor until surgery.

In our practices, we only infuse a GP IIb/IIIa inhibitor during PCI or possibly up to four hours afterwards. One strategy is to infuse the GP IIb/IIIa inhibitor until a P2Y₁₂ inhibitor takes effect. In unusual cases of large thrombus burden or intraprocedural thrombotic events, we may use a longer duration of therapy that is determined by the patient's characteristics.

Trials of treatment with a GP IIb/IIIa inhibitor prior to angiography found no benefit and an increased risk of bleeding [29,30]. The other indications for use are based on expert consensus.

Oral P2Y12 inhibitor not available prior to PCI — In patients with NSTEACS who cannot be adequately pretreated with a P2Y₁₂ inhibitor prior to PCI, which is rare, cangrelor is an option for therapy either prior to or after PCI.

This approach is consistent with North American and European guidelines [1,2].

Cangrelor is an intravenous P2Y₁₂ inhibitor with almost immediate onset of platelet inhibition. We do not routinely use cangrelor due to its small benefit and increased risk of bleeding. Instead, we favor treatment with an oral P2Y₁₂ inhibitor prior to PCI. Cangrelor was compared with either clopidogrel or placebo in three randomized trials that included patients with NSTEACS. In a meta-analysis of these trials, patients assigned to cangrelor had a decreased rate of recurrent MI at 14 days (3.1 versus 3.6 percent for clopidogrel; OR 0.85, 95% CI 0.74-0.97) and similar rates of death (0.3 versus 0.4 percent) [31]. There was an increase in the rate of mild bleeding (16.8 versus 13 percent; OR 1.4, 95% CI 1.3-1.5) but no increase in the rate major bleeding (0.2 percent in both groups).

USE OF SPECIFIC AGENTS

Aspirin — The dosing of aspirin and management of patients with aspirin allergy are as follows:

●Dosing – The initial dose of aspirin for suspected or confirmed NSTEMI is 325 mg of uncoated aspirin. The first tablet should be chewed or crushed to improve absorption. After the first dose of aspirin, we give a daily dose of 75 to 81 mg per day rather than prescribe a higher dose. There is no benefit from a higher dose, and there is a higher risk of bleeding, particularly from the gastrointestinal tract [4,32,33]. In one study of data from a large trial, patients randomly assigned to ticagrelor who were treated with high-dose aspirin had higher rates of a combined endpoint of cardiovascular mortality, recurrent MI, or stroke compared with other groups in the trial (ie, ticagrelor plus lower-dose aspirin, clopidogrel regardless of aspirin dose) [34].

●Aspirin allergy – For patients with a history of aspirin allergy, it is reasonable to administer a P2Y₁₂ receptor blocker alone. When used as monotherapy, the contributors to this topic prefer prasugrel or ticagrelor rather than clopidogrel. When the patient is stable, an evaluation for possible aspirin desensitization can be performed by an allergy expert. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions", section on 'Indications for urgent aspirin therapy'.)

Prasugrel — Prasugrel is most appropriate for use in patients who will or did undergo percutaneous coronary intervention (PCI). (See 'Invasive strategy' above.)

We give a loading dose of 60 mg and maintenance dose of 10 mg daily. Our experts reduce the dose to 5 mg daily in patients ≥75 years or who weigh less than 60 kg, as was evaluated in the TRILOGY trial. (See 'Older patients and low body weight' above and 'Choice of agent' above.)

Patients with NSTEACS and prior stroke or transient ischemic attack should be treated with an alternate P2Y₁₂ inhibitor. (See 'Cerebrovascular disease' above.)

Ticagrelor — We give a loading dose of 180 mg and a maintenance dose of 90 mg twice daily. For those patients who will be continued on ticagrelor after 12 months from the diagnosis, the dose is reduced to 60 mg twice daily, as studied in the PEGASUS trial and PLATO trials and as approved by the US Food and Drug Administration [15,35].

Clopidogrel — The use of clopidogrel depends on the management strategy:

Noninvasive management — For patients managed with a noninvasive strategy, we give a loading dose of 300 mg followed by 75 mg daily. We provide this loading dose regardless of clopidogrel treatment prior to the acute MI presentation. In a large trial, patients treated with a 300 mg or 600 mg loading dose had similar rates of death or recurrent MI [32]. In the subgroup of patients managed medically, the rate of the primary outcome (death, MI, or stroke) was lower in patients assigned to receive the 300 mg loading dose (4.3 versus 4.9 percent).

Invasive management — For patients who will undergo PCI, prasugrel or ticagrelor are the preferred agents regardless of prior treatment with clopidogrel. (See 'Choice of agent' above.)

In patients managed with an invasive strategy and dual antiplatelet therapy with clopidogrel, the dosing prior to angiography is as follows:

●Angiography in less than six hours – In patients who will undergo coronary angiography within the next six hours, we give a 600 mg loading dose prior to angiography. After PCI, the maintenance dose of clopidogrel is 75 mg daily.

This approach is based relative weak evidence from two trials:

•The CURRENT-OASIS 7 trial included 25,086 patients who were randomly assigned to a higher loading dose (600 mg) and initial maintenance dose (150 mg) of clopidogrel or to a standard loading dose (300 mg) and initial maintenance dose (75 mg daily) of clopidogrel. The overall trial found similar rates of the primary outcome of death, MI, or stroke but a lower rate of the primary outcome in a subgroup analysis of patients who underwent PCI who received the higher loading dose (3.9 versus 4.5 percent) [32].

•In the ARMYDA trial, 255 patients with NSTEACS who underwent PCI were assigned to a 600 mg loading dose or to a 300 mg loading dose of clopidogrel; the rate of recurrent MI was lower in the group assigned to receive a 600 mg loading dose (4 versus 8 percent) [36].

●Angiography beyond eight hours – In patients who will not undergo coronary angiography within the next eight hours, we give a 300 mg loading dose of clopidogrel. The maintenance dose of clopidogrel is 75 mg daily.

Role of genetic testing — We do not perform routine testing for genotypes associated with clopidogrel hyporesponsiveness. This issue is discussed elsewhere. (See "Clopidogrel resistance and clopidogrel treatment failure".)

OTHER ASPECTS OF ANTIPLATELET THERAPY

Duration of therapy — Upon discharge from the index hospitalization for NSTEACS, we prefer to treat all patients with NSTEACS with dual antiplatelet therapy (the combination of aspirin plus a P2Y₁₂ inhibitor). (See 'Initial therapy (dual antiplatelet therapy)' above.)

Within the first month of the diagnosis of NSTEACS, we recommend reassessing the patient to determine the appropriate long-term antiplatelet regimen. The details on long-term antiplatelet therapy are discussed elsewhere. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Duration'.)

Switching agents

●Ticagrelor or prasugrel to clopidogrel – Either ticagrelor or prasugrel is preferred to clopidogrel as the initial P2Y₁₂ inhibitor in patients with NSTEMI. However, as many as 10 percent of patients may need to switch to clopidogrel due to reasons such as increased bleeding risk, nonbleeding side effects, and cost [37-39]. We advocate the following strategies [38,40]:

•Ticagrelor to clopidogrel – For patients taking ticagrelor, we give the first dose of clopidogrel 12 hours after the last dose of ticagrelor. We give a 600 mg loading dose of clopidogrel to all such patients [41].

•Prasugrel to clopidogrel – For patients taking prasugrel for five days or less, some of our experts load with clopidogrel 300 mg 24 hours after the last dose of prasugrel, while others do not load and replace the prasugrel maintenance dose with the clopidogrel maintenance dose.

For patients who have received prasugrel for more than five days, we start clopidogrel 75 mg daily 24 hours after the last dose of prasugrel.

●Switching to ticagrelor – When switching from clopidogrel or prasugrel to ticagrelor after NSTEACS, we give ticagrelor 180 mg (loading dose) at any time within 24 hours after the last dose of clopidogrel or prasugrel. Then, we give ticagrelor 90 mg twice daily beginning approximately 12 hours later.

Prevention of ulcers — For patients with a history of or who are at high risk for gastrointestinal bleeding, drugs that reduce the risk of recurrent bleeding (eg, proton pump inhibitors) should be given. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)".)

SUMMARY AND RECOMMENDATIONS

●Initial antiplatelet therapy – In patients with non-ST-elevation acute coronary syndromes (NSTEACS), we recommend treatment with aspirin plus a P2Y₁₂ inhibitor (eg, ticagrelor, prasugrel) rather than aspirin alone (Grade 1B). (See 'Initial therapy (dual antiplatelet therapy)' above.)

The dosing of aspirin is an initial dose of 325 mg followed by 81 to 100 mg daily. (See 'Aspirin' above.)

The timing of therapy and choice of P2Y₁₂ agents depends on the strategy (algorithm 1) used to manage NSTEACS (algorithm 1):

•Invasive strategy – In patients managed with an invasive strategy, the timing of therapy and choice of agent are as follows:

-Timing of therapy – For patients with NSTEACS who will undergo an invasive strategy (algorithm 1), we suggest treatment with a P2Y₁₂ inhibitor after coronary angiography and prior to percutaneous coronary intervention (PCI) rather than prior to coronary angiography (Grade 2C). In patients who are likely to have a delay of at least 24 hours from the time of diagnosis until coronary angiography, it is reasonable to begin P2Y₁₂ inhibitor therapy at the time of diagnosis of NSTEACS. (See 'Timing of therapy' above.)

In patients who undergo angiography but do not undergo PCI, the approach to antiplatelet therapy depends on the next steps in management. Patients managed medically should receive antiplatelet therapy similar to patients managed with a noninvasive strategy, while patients who will undergo coronary artery bypass graft surgery (CABG) typically receive an individualized approach to antiplatelet therapy based on the timing of surgery. (See 'Noninvasive strategy' above and 'Therapy prior to CABG' above.)

-Choice of agent – The choice of agent depends on the timing of therapy. In patients who will be managed with an invasive strategy that includes dual antiplatelet therapy (DAPT; aspirin plus a P2Y₁₂ inhibitor) after angiography and prior to PCI, we recommend prasugrel or ticagrelor rather than clopidogrel (Grade 1B).

In patients who will receive DAPT prior to planned angiography, we recommend ticagrelor rather than clopidogrel (Grade 1B). Prasugrel is typically not used for pretreatment due to a higher rate of bleeding. (See 'Choice of agent' above.)

The dosing of these agents is discussed individually. (See 'Use of specific agents' above.)

•Noninvasive strategy – For patients managed with a noninvasive strategy (algorithm 1) and DAPT, we suggest ticagrelor rather than clopidogrel (Grade 1B). In patients who cannot take ticagrelor, treatment with clopidogrel is a reasonable option. Prasugrel is typically not used for noninvasive management due to a higher rate of bleeding. Therapy with DAPT should begin as soon as the decision is made to pursue a noninvasive strategy. (See 'Noninvasive strategy' above.)

The dosing regimens for these agents are discussed individually. (See 'Use of specific agents' above.)

●Special circumstances

•Older patients and low body weight – Most patients ≥75 years of age and those with body weight ≥60 kg can be treated with the usual regimen and dose of antiplatelet therapy (eg, aspirin plus a P2Y₁₂ inhibitor), but in patients ≥75 years of age or who weigh less than 60 kg and who will be treated with prasugrel, we use a lower maintenance dose (eg, 5 mg rather than 10 mg daily). (See 'Prasugrel' above.)

•Cerebrovascular disease – In patients with cerebrovascular disease, prasugrel should be avoided. (See 'Cerebrovascular disease' above.)

•Patients taking oral anticoagulants – In the acute management of ACS in patients with long-term needs for anticoagulation (eg, mechanical valve), the approach to therapy includes DAPT as indicated for the management strategy of choice. (See 'Invasive strategy' above and 'Noninvasive strategy' above.)

After acute management concludes (eg, stenting, normal stress testing, index hospitalization), a decision on the intensity of antithrombotic therapy must be made. The approach to long-term therapy with oral anticoagulation plus a P2Y₁₂ inhibitor with or without aspirin is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients", section on 'Rivaroxaban'.)

•Therapy prior to CABG – P2Y₁₂ inhibitors should be discontinued prior to CABG to reduce the risk of operative bleeding. For patients treated with prasugrel, we stop therapy at least seven days prior to surgery. For patients treated with ticagrelor or clopidogrel, we stop therapy at least five days before surgery.

In patients receiving a glycoprotein (GP) IIb/IIIa inhibitor, it should be discontinued at least two to four hours before surgery. (See 'Therapy prior to CABG' above.)

•High-risk scenarios – We avoid use of GP IIb/IIIa inhibitors prior to angiography or PCI. Scenarios in which a GP IIb/IIIa inhibitor may be beneficial include persistent evidence of ischemia despite DAPT, high-risk findings at angiography (eg, thrombus), or complications of coronary intervention. (See 'High-risk scenarios' above.)

•Inability to take a P2Y12 inhibitor prior to PCI – In patients with NSTEACS who cannot be adequately pretreated with a P2Y₁₂ inhibitor prior to PCI, which is rare, cangrelor is an option for therapy either prior to or after PCI. (See 'Oral P2Y12 inhibitor not available prior to PCI' above.)

●Other aspects of antiplatelet therapy

•Duration of therapy – Upon discharge from the index event, we prefer to treat all patients with NSTEACS with DAPT (the combination of aspirin plus a P2Y₁₂ inhibitor). (See 'Initial therapy (dual antiplatelet therapy)' above.)

Within the first month of the diagnosis of NSTEACS, we recommend reassessing the patient to determine the appropriate long-term antiplatelet regimen. The details on long-term antiplatelet therapy are discussed elsewhere. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Duration'.)

•Switching agents – The approach to switching between agents is described above. (See 'Switching agents' above.)

•Prevention of gastric ulcers – For patients with a history of or who are at high risk for gastrointestinal bleeding, drugs that reduce the risk of recurrent bleeding (eg, proton pump inhibitors) should be given. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Simons, MD, who contributed to earlier versions of this topic review.