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

Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy
Literature review current through: Aug 2023.
This topic last updated: May 13, 2021.

INTRODUCTION — This topic addresses the use of antiplatelet therapy in patients with an acute non-ST-elevation acute coronary syndromes (NSTEACS) at the time of diagnosis and at hospital discharge.

Other relevant topics include:

(See "Mechanisms of acute coronary syndromes related to atherosclerosis".)

(See "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

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

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

OUR APPROACH TO EARLY P2Y12 RECEPTOR BLOCKER — Most patients with acute NSTEACS should be treated with a P2Y12 receptor blocker (inhibitor). The choice and timing of administration of the P2Y12 receptor blocker depend on whether an invasive or an ischemia-guided (conservative) management strategy is chosen (see 'Invasive management' below and 'Ischemia-guided management' below and "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization"):

For NSTEACS patients assigned to an invasive strategy, our approach to the use of P2Y12 inhibitor depends on the likely timing of diagnostic angiography:

For patients in whom angiography is anticipated to occur within a short time after presentation (on the day of or within a few hours), we usually delay treatment with a P2Y12 receptor blocker until the anatomy is known.

For patients who are likely to experience a longer delay before undergoing coronary angiography and possible PCI, either pretreatment with a P2Y12 receptor blocker (ticagrelor) or waiting until after angiography (ticagrelor or prasugrel) is a reasonable strategy.

For patients assigned to an ischemia-guided (conservative) strategy, we give a loading dose of ticagrelor 180 mg at the time of diagnosis or as soon as possible thereafter.

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".)

RATIONALE — The rationale for early dual antiplatelet therapy (DAPT) is that platelet adhesion and aggregation are early steps in the formation of occlusive coronary artery thrombus (see "The role of platelets in coronary heart disease"). DAPT is directed at limiting these early steps, which might result in thrombus occlusion of a coronary artery or stent thrombosis in those patients who are stented. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

The benefit of DAPT was established in the CURE trial, which randomly assigned 12,562 patients who presented within 24 hours after the onset of a NSTEACS to aspirin alone (75 to 325 mg/day) or with clopidogrel (300 mg loading dose immediately followed by 75 mg/day) for 3 to 12 months; both were given immediately on presentation. The majority of patients were at increased risk of an adverse outcome because of electrocardiogram changes (mostly ST depression ≥1 mm or T wave inversion ≥2 mm) or elevated cardiac enzymes [1]. Over 60 percent did not receive revascularization. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke.

At an average follow-up of nine months, combination therapy led to a significant reduction in the combined primary endpoint of cardiovascular death, nonfatal MI, or stroke (9.3 versus 11.4 percent), which was largely due to fewer MIs (5.2 versus 6.7 percent) (figure 1). However, clopidogrel therapy significantly increased the rate of major bleeding (3.7 versus 2.7 percent) but not life-threatening bleeding or hemorrhagic stroke. This risk (5 per 1000) was much smaller than the cardiovascular benefit (22 per 1000).

Clopidogrel therapy produced a similar relative risk reduction in patients who were treated medically or underwent revascularization [2] and in low-, intermediate-, and high-risk patients as defined by the Thrombolysis In Myocardial Infarction risk score (calculator 1) [3]. High-risk patients derived the greatest absolute benefit.

ASPIRIN FOR ALL PATIENTS — Aspirin has established efficacy and safety in the acute therapy of patients with NSTEACS [4]. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

A loading dose of 325 mg of uncoated aspirin should be given as soon as possible to any patient with NSTEACS, including those taking chronic low-dose aspirin therapy and irrespective of treatment strategy [5]. The first tablet should be chewed or crushed to establish a high blood level quickly. More rapid absorption occurs with nonenteric-coated formulations. After the loading dose, we prescribe aspirin at a dose of 75 to 81 mg/day rather than higher doses since there is no benefit from a higher dose, and there is a higher risk of bleeding, particularly from the gastrointestinal tract [1,6,7].

This recommendation for low-dose aspirin is particularly important in patients taking ticagrelor. In these patients, aspirin must be given at a dose of ≤100 mg daily, based on results in the PLATO study [8] and as listed in the United States Food and Drug Administration package insert for the drug. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'P2Y12 use'.)

For patients with a history of possible aspirin allergy, the optimal approach is not known. In patients who cannot be desensitized before the procedure, we administer a P2Y12 receptor blocker alone. Most experts prefer one of the more potent agents (eg, prasugrel or ticagrelor) over clopidogrel for those patients in whom clopidogrel would ordinarily be chosen. 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'.)

Aspirin therapy may be associated with gastrointestinal intolerance, including bleeding, allergy (primarily manifested as bronchospasm or asthma), or worsening of preexistent bleeding outside the gastrointestinal tract. Additional information regarding aspirin use is found elsewhere. (See "Gastrointestinal bleeding in patients undergoing percutaneous coronary intervention" and "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions", section on 'Indications for urgent aspirin therapy'.)

INVASIVE MANAGEMENT — This section provides the evidence supporting our recommendations (see 'Our approach to early P2Y12 receptor blocker' above) for the timing of initiation and the choice of P2Y12 receptor blocker in patients undergoing an invasive strategy, rather than an ischemia-guided (conservative) management strategy. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization", section on 'Clinically stable patients' and 'Ischemia-guided management' below.)

For patients in whom an invasive strategy will be carried out, coronary angiography may be performed within 3 hours (immediate), 3 to 24 hours (an early invasive approach), and within 48 hours (a delayed invasive approach). These time intervals are arbitrary. For most patients undergoing an early invasive approach, we often perform angiography well before the 24-hour mark. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization".)

All NSTEACS patients who undergo percutaneous coronary intervention (PCI) with stenting should receive a P2Y12 inhibitor. Ticagrelor 180 mg or prasugrel 60 mg is preferred to clopidogrel in most cases. If the drug is given prior to angiography, we do not use prasugrel.

For patients who receive immediate coronary angiography (within three hours of the diagnosis) or an early invasive approach (within 24 hours), we often wait until after angiography to start a P2Y12 receptor blocker if PCI is to be performed. For these patients who appear to be at high ischemic risk, we consider pretreatment with a P2Y12 receptor blocker if coronary angiography will be significantly delayed. With pretreatment, bleeding risk needs to be taken into account.

Most patients who undergo a delayed invasive approach (after 24 hours) are lower-risk patients and may benefit less from pretreatment than higher-risk patients while exposing them to the risk of bleeding. Based on expert opinion, rather than well-performed studies, either pretreatment with a P2Y12 receptor blocker or waiting until after angiography is a reasonable strategy.

Timing — For many patients undergoing an invasive approach, we delay giving a P2Y12 inhibitor until after diagnostic angiography confirms a need for PCI. This practice is primarily based on findings in three randomized trials (presented below) that had significantly different designs and end points. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Timing and dose'.)

Early invasive management — Patients scheduled for an early invasive approach are also scheduled for coronary angiography before 24 hours. In most cases, we prefer to take them to the catheterization laboratory much sooner than 24 hours.

A proposed argument in favor of early (at the time of diagnosis) treatment has been that pretreatment would lower the risk of a recurrent ischemic event before PCI or reduce the risk of PCI-related thrombotic complications. Early support for this point of view came in part from the CURE trial that randomly assigned nearly 13,000 aspirin-treated ACS patients to clopidogrel or placebo within 24 hours of hospitalization. The proportion of patients experiencing cardiovascular death, MI, or stroke at 30 days was 5.4 percent in the placebo group and 4.3 percent in the active group (relative risk 0.79, 95% CI 0.67-0.92), and event rates diverged within a few hours in favor of early clopidogrel use [9]. This finding was also seen in a subgroup analysis of the 2658 patients who underwent PCI [2]. This finding was also supported by 2012 meta-analysis of studies of that included NSTEACS patients [10]. It found that although clopidogrel pretreatment, compared with treatment after catheterization, was not associated with a reduction in mortality (absolute risk 1.54 versus 1.97 percent, respectively, odds ratio [OR] 0.80, 95% CI 0.57-1.11), it was associated with a lower risk of a secondary composite end point of death, myocardial infarction (MI), stroke, or urgent revascularization (9.83 versus 12.35 percent, OR 0.77, 95% CI 0.66-0.89). In these studies, clopidogrel was the P2Y12 inhibitor used. Since ticagrelor or prasugrel have been shown to be superior to clopidogrel in ACS patients, we do not weigh these data heavily in our assessment of optimal timing. Two earlier studies comparing pretreatment with treatment after angiography using clopidogrel in stable patients suggested treatment prior to PCI was more effective [11,12].

An argument against early pretreatment is that about 35 percent of patients do not undergo PCI, including patients with noncardiac diagnoses. Delaying P2Y12 inhibitor therapy eliminates the well-documented risk of bleeding attributable to the P2Y12 inhibitor [13,14].

Three randomized trials that used either ticagrelor, prasugrel, or both have compared pretreatment with treatment after coronary angiography:

The ACCOAST trial randomly assigned 4033 patients with non-ST-elevation MI (NSTEMI) who were scheduled to undergo an invasive approach within 2 to 48 hours to prasugrel 30 mg before angiography or placebo [15]. For patients undergoing PCI after angiography, an additional 30 mg was given to those in the pretreatment group and 60 mg to those given placebo, and all patients received prasugrel 10 mg daily thereafter; P2Y12 therapy for those treated medically or with CABG was left to the discretion of the investigator. PCI was performed at a mean time of 4.3 hours after the initial loading dose. The trial was stopped early because of the finding of harm. At seven days, the rate of the primary composite efficacy end point (death from cardiovascular causes, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy) was similar in the two groups (10.0 versus 9.9 percent, respectively; hazard ratio [HR] 1.02, 95% CI 0.84-1.25). However, the rate of the key safety end point of all TIMI major bleeding episodes was greater with pretreatment (2.6 versus 1.4 percent; HR 1.90, 95% CI 1.19-3.02). The results were similar in the subgroup of patients undergoing PCI. In an analysis of only those patients who received PCI (68 percent), the results were similar: There was no difference in the primary end point (13.1 percent), while the rate of major bleeding was greater with pretreatment (1.4 versus 0.5 percent) [13].

The open-label DUBIUS trial randomly assigned 1449 patients with NSTEACS scheduled to undergo an invasive strategy to ticagrelor before angiography or to either ticagrelor or prasugrel after angiography [16]. There was no difference in the rate of the primary composite end point (death due to vascular causes, nonfatal MI, or nonfatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleeding through day 30). The study was stopped early for futility. Additional limitations of this trial include short follow-up and a very small number of events.

The open-label ISAR-REACT 5 trial randomly assigned 4018 patients with ACS (59 percent NSTEACS) and planned invasive evaluation to ticagrelor or prasugrel [17,18]. In patients with NSTEACS, the loading dose of ticagrelor was given as soon as possible after randomization; the loading dose of prasugrel was delayed until after coronary angiography. The time between randomization and loading dose was 6 and 61 minutes for the two drugs, respectively. Thus, in ISAR-REACT 5, patients with NSTEACS in whom an invasive strategy was planned were on average taken to the catheterization laboratory very quickly. The primary end point (a composite of death, MI, or stroke at one year) occurred more often in patients who received ticagrelor (9.3 versus 6.9 percent, respectively; HR 1.36, 95% CI 1.09-1.70). There was a nonsignificant trend toward a higher rate of death from any cause in the ticagrelor group (90 versus 73 deaths; 4.5 versus 3.7 percent, HR 1.23, 95% CI 0.91-1.68). Major bleeding as defined as BARC 3, 4, or 5 (table 1) occurred with similar frequency in both groups (5.4 and 4.8 percent, respectively). Limitations of the trial include open-label design (compared with the TRITON-TIMI 38 and PLATO trials) (see 'Choice of drug' below) and telephone follow-up in more than 90 percent of patients.

Delayed invasive approach — In general, patients whose coronary angiography is delayed are at lower ischemic risk. Pretreatment may add bleeding risk to this group, which benefits less from pretreatment due to the lower ischemic risk. Our contributors believe that pretreatment with ticagrelor 180 mg or no pretreatment is a reasonable approach.

Choice of drug — The evidence that either prasugrel or ticagrelor is preferred to clopidogrel comes from two large randomized trials:

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 [19]. In the majority of cases, both clopidogrel and prasugrel were given after coronary angiography.

At 15-month follow-up, the primary efficacy end point (cardiovascular death, nonfatal MI, or nonfatal stroke) occurred significantly less often in patients treated with prasugrel (9.9 versus 12.1 percent; HR 0.81; 95% CI 0.73-0.90) [19,20]. This was driven primarily by a significant reduction in nonfatal MI (7.4 versus 9.7 percent).

The safety end point of a major bleeding event not associated with coronary artery bypass graft surgery (CABG) occurred significantly more often in patients treated with prasugrel (2.4 versus 1.8 percent; HR 1.32; 95% CI 1.03-1.68). This difference was attributable to an increase in bleeding events with prasugrel after (but not before) the first three days [21]. The rate of life-threatening bleeding was also significantly increased with prasugrel. In addition, the rates of transfusion and reoperation after CABG were significantly increased with prasugrel.

The PLATO trial compared ticagrelor with clopidogrel in 18,624 ACS patients (43 percent of whom had NSTEMI) randomly assigned on presentation, regardless of revascularization strategy [8]. Unlike the protocol in the TRITON-TIMI 38 trial, treatment was started as soon as possible after hospital admission (median of five hours), but many patients received the drug after coronary angiography. The median time from the first dose of the study drug to PCI was approximately four hours (interquartile range [approximately] 0.45 to 50.8 hours). PLATO included patients who underwent PCI, were referred for CABG, or were managed medically.

At 12 months, the composite primary end point (first event of death from vascular causes, MI, or stroke) occurred significantly less often in patients receiving ticagrelor (9.8 versus 11.7 percent, HR 0.84, 95% CI 0.77-0.92). There was no significant difference in the rates of major bleeding between the ticagrelor and clopidogrel groups (11.6 versus 11.2 percent, respectively), nor were there differences in transfusion rates, although ticagrelor was associated with a significantly higher rate of major bleeding not related to CABG (4.5 versus 3.8 percent).

The finding of a lower risk of ischemic events with prasugrel compared with ticagrelor in ISAR-REACT 5 (see 'Timing' above) was not predicted based on the results of the older TRITON-TIMI 38 and PLATO trials, where clopidogrel is the comparator and where ISAR-REACT 5 is a head-to-head comparison. We are uncertain as to why the two drugs were not found to have similar ischemic outcomes. Possible explanations include:

The above limitations of ISAR-REACT 5.

Differing patient populations or cointerventions between TRITON-TIMI 38 and PLATO trials and ISAR-REACT 5.

Until further evidence is available to support or refute the superiority of prasugrel, we believe that either prasugrel or ticagrelor is a reasonable choice (and superior to clopidogrel) for patients with NSTEACS who undergo diagnostic angiography within 24 hours [22]. However, prasugrel should not be administered before the invasive procedure given the protocols used in the TRITON-TIMI 38 and ISAR-REACT 5 trials.

Glycoprotein IIb/IIIa inhibitors — Most patients with NSTEACS scheduled for PCI do not require glycoprotein (GP) IIb/IIIa inhibitor therapy. This is particularly true if they have received a potent P2Y12 inhibitor (prasugrel or ticagrelor) rather than clopidogrel [23-25]. A GP IIb/IIIa inhibitor may be considered for some high-risk patients, although the evidence to support doing so is weak; it is based on expert consensus:

Patients who have received aspirin and a potent P2Y12 inhibitor and who have evidence of ongoing ischemia (eg, persistent chest pain and electrocardiographic evidence of ischemia).

Patients who have high-risk features during angiography such as large thrombus burden or intraprocedural thrombotic complication, particularly if they have not received prasugrel or ticagrelor.

In patients for whom CABG is likely to be required urgently after coronary angiography, acute administration of a GP IIb/IIIa inhibitor may be substituted for a P2Y12 inhibitor to stabilize patients until operative indications have been defined.

GP IIb/IIIa inhibitors are not started until after diagnostic coronary angiography in most cases, based on the ACUITY Timing and EARLY ACS trials, which found no benefit from early initiation and an increased risk of bleeding with preangiography use [24,25].

For those high-risk patients in whom the use of GP IIb/IIIa inhibitors is reasonable, we use the following dosing regimens for tirofiban (high-dose regimen is preferred) and eptifibatide, which are based on regimens used in clinical trials:

Tirofiban – For patients with NSTEACS, whether undergoing an invasive or an ischemia-guided strategy, a loading dose of 25 mcg/kg (referred to as the high-bolus dose) over five minutes or less, which should be followed by a continuous infusion of 0.15 mcg/kg/min, which is continued for up to 18 hours.

The infusion dose should be reduced by 50 percent in patients with an estimated creatinine clearance of ≤60 mL/min.

Eptifibatide – A loading dose of 180 mcg/kg (maximum: 22.6 mg) over one to two minutes should be followed by a continuous infusion of 2 mcg/kg/min (maximum: 15 mg/hour), which is continued for 18 to 24 hours. A second 180 mcg/kg bolus should be given 10 minutes after the first bolus.

The continuous infusion should be reduced by 50 percent in patients with estimated creatinine clearance <50 mL/min.

In our practices, we generally limit the infusion to the duration of the procedure or possibly up to four hours afterwards, with an objective of providing adequate antiplatelet therapy until the full effect of the loaded P2Y12 inhibitor occurs. In unusual cases of large thrombus burden or intraprocedural thrombotic events, we may use the longer durations as specified above.

ISCHEMIA-GUIDED MANAGEMENT — Ischemia-guided or conservative management refers to the strategy of an initial attempt at medical management; persistence of symptoms, symptom recurrence, or a positive stress test should lead to prompt cardiac catheterization. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization".)

For patients managed conservatively, we give ticagrelor (plus aspirin) at the time of diagnosis in most cases. For patients in whom ticagrelor cannot be used, we suggest using clopidogrel. These preferences are based on superior efficacy of ticagrelor over clopidogrel, as well as a trend toward lower rates of bleeding with clopidogrel compared with prasugrel.

In the PLATO trial (see 'Invasive management' above), the incidence of the primary end point was lower with ticagrelor than clopidogrel in the subgroup of patients with a planned noninvasive management (12.0 versus 14.3 percent; hazard ratio [HR] 0.85, 95% CI 0.73-1.00) [26].

The TRILOGY ACS trial directly compared prasugrel with clopidogrel in 9326 patients treated with aspirin, who had NSTEACS, and in whom percutaneous coronary intervention was not performed [27]. Prasugrel was given with a loading dose of 30 mg and a maintenance dose of 10 mg/day in patients less than 75 years old or 5 mg/day for those 75 years or older or who weighed less than 60 kg.

There was no statistically significant difference in the rate of cardiovascular death, MI, or stroke in the 7243 patients under the age of 75 years between those who received prasugrel and those who received clopidogrel (13.9 versus 16.0 percent; HR 0.91, 95% CI 0.79-1.05).

The rates of severe and intracranial bleeding were not significantly different. However, irrespective of which bleeding criteria were applied, the event rates at 30 days tended to be higher with prasugrel, and the confidence intervals for the hazard ratios for bleeding often included upper boundaries that indicated as much as a doubling of the risk.

A separate analysis of the 2083 individuals ≥75 years of age found that the risks of the primary end point and of TIMI major bleeding increased progressively with age and were two– to threefold higher in older individuals, irrespective of the P2Y12 inhibitor [28].

POSSIBLE EARLY CABG — For NSTEACS patients who undergo early coronary artery bypass graft surgery (CABG) and are receiving dual antiplatelet therapy (DAPT), there is a concern for an increased risk of perioperative bleeding with DAPT. We do not believe, however, that this concern should prevent administration of P2Y12 inhibitors prior to coronary angiography in ACS patients for whom revascularization decisions have not yet been made. Any excess bleeding risk due to recent P2Y12 inhibitor use in the minority of patients who will or might require urgent/immediate CABG must be weighed against the potentially deleterious effect of not administering such therapy early to the vast majority of patients who will not require immediate surgery [29].

For most patients, we suggest discontinuing P2Y12 inhibitor before CABG (at least five days for ticagrelor and clopidogrel and at least seven days for prasugrel) [30,31]. There is some evidence to suggest that discontinuation of ticagrelor within three days of surgery may be a reasonable strategy [30].

The following studies inform our recommendation regarding the timing of discontinuation of P2Y12 inhibitor:

The likelihood of CURE-defined major bleeding within seven days of CABG was nonsignificantly increased in patients in the CURE trial who had 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) [32]. This finding is supported by several observational studies [33-37]. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Bleeding'.)

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 [38]. 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 ratios 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).

In subgroup analyses of patients undergoing CABG in the CURE trial [32], patients with ACS who received clopidogrel had a lower rate of adverse outcomes than those who did not. (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes", section on 'Unfractionated heparin compared with bivalirudin'.)

In patients receiving a glycoprotein IIb/IIIa inhibitor, it should be discontinued for at least two to four hours before surgery [39].

P2Y12 USE

Dose — We use the following P2Y12 inhibitor dosing regimens in patients with NSTEACS. These regimens are generally consistent with the doses used in the randomized trials:

Prasugrel – We give a loading dose of 60 mg and maintenance dose of 10 mg/day in most patients. Reducing the maintenance dose to 5 mg/day (and continuing aspirin) after one month can be considered in Asian patients as an option for reducing DAPT intensity and decreasing bleeding risk. Our experts would also consider reducing the dose to 5 mg/day in patients 75 years or older or who weigh less than 60 kg, as was evaluated in the TRILOGY trial. (See 'Ischemia-guided management' above.)

East Asian individuals are known to be at higher-than-average bleeding risk. In the HOST-REDUCE-POLYTECH-ACS trial, 2338 east Asian patients with ACS undergoing PCI were randomly assigned to 5 or 10 mg of prasugrel daily after one month of 10 mg daily [40]. All patients received aspirin 100 mg daily from percutaneous coronary intervention (PCI) until the end of the study. The following was found at one year:

There was no difference between the two groups in the rate of all-cause death (10 versus 14 events, respectively; 0.9 versus 1.2 percent, hazard ratio [HR] 0.71, 95% CI 0.32-1.60) or nonfatal MI (7 versus 8 events; HR 0.6 versus 0.7 percent, HR 0.87, 95% CI 0.32-2.40).

Although the risk of Bleeding Academic Research Consortium (BARC) bleeding grade ≥2 (table 1) was lower with the 5 mg dose (33 versus 67 events, respectively; 2.9 versus 5.9 percent, HR 0.48, 95% CI 0.32-0.73), there was no difference in the rate of BARC bleeding grade ≥3 (9 versus 8 events, respectively; p = 0.82).

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, our contributors reduce the dose to 60 mg twice daily.

Clopidogrel – We give a loading dose of 600 mg and a maintenance dose of 75 mg daily. Two trials (ARMYDA and CURRENT-OASIS 7) compared clopidogrel 600 mg with 300 mg and found that the rate of ischemic events, particularly in patients who undergo PCI, is lower with the 600 mg dose [6,41].

For those patients who received clopidogrel prior to diagnostic angiography or who have been taking clopidogrel long term, we suggest switching to ticagrelor or prasugrel (with appropriate loading doses) prior to or after PCI, depending on bleeding risk and presence of contraindications.

Method of administration — Ticagrelor and prasugrel, which are our preferred P2Y12 inhibitors, are given orally (tablet). There is evidence that, compared with whole tablets, administration of crushed ticagrelor tablets leads to significantly higher plasma concentrations at earlier time points and earlier platelet inhibition [42-44]. No study has shown evidence of an improvement in clinical outcomes. We believe it is reasonable to administer crushed ticagrelor to patients who are unable to swallow tablets, such as those who are intubated. Most of our experts have not begun the routine administration of crushed ticagrelor.

Duration — We treat all NSTEACS patients with DAPT (the combination of aspirin plus a P2Y12 inhibitor) for at least 12 months unless there has been a significant bleeding episode or if there is a very high bleeding risk (see 'Our approach to early P2Y12 receptor blocker' above). However, there is some evidence that a shorter duration (eg, less than 12 months and perhaps less than six months) of DAPT followed by P2Y12 inhibitor monotherapy may be a reasonable approach, particularly in patients at high bleeding risk. This is discussed in detail elsewhere. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment'.)

Evidence for continuing DAPT for 12 months rather than for shorter duration (with continuation of aspirin monotherapy) comes from the SMART-DATE trial [45].

In the SMART-DATE trial, 2712 patients with ACS (about 60 percent NSTEACS) who underwent PCI were randomly assigned to 6 or 12 months or longer of DAPT with aspirin and a P2Y12 inhibitor (clopidogrel in 80 percent) [45]. The primary combined end point (all-cause death, MI, or stroke at 18 months) occurred at a similar rate in the two groups (4.7 and 4.2 percent, respectively; HR 1.13, 95% CI 0.79-1.62). The secondary end point of spontaneous MI occurred significantly more often in the six-month group (1.8 versus 0.8 percent; HR 2.41, 95% CI 1.15-5.05). The risk of BARC type 2 to 5 bleeding was significantly lower in the six-month group (2.3 versus 3.8 percent; HR 0.60, 95% CI 0.36-0.99). A few limitations of this study include relatively small sample size, the use of clopidogrel rather than ticagrelor or prasugrel, and a high cross-over rate in the six-month group. SMART-DATE does not support routine treatment with a P2Y12 inhibitor for six months but rather gives some reassurance that six months is a reasonable duration of DAPT in patients at high bleeding risk.

In patients who have received DAPT successfully for 12 months, we continue treatment for as long as an additional 36 months. Evidence of benefit from more than 12 months of DAPT comes from the DAPT and PEGASUS-TIMI 54 trials:

The DAPT trial compared 18 months of DAPT (aspirin plus either clopidogrel or prasugrel) with aspirin alone in stented patients who had received DAPT for 12 months without major complication [46]. Approximately 32 percent of the nearly 10,000 patients had NSTEACS. The rates for each of the coprimary end points of stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death from any cause, MI, or stroke) were lower with continued P2Y12 therapy (0.4 versus 1.4 percent; HR 0.29, 95% CI 0.17-0.48 and 4.3 versus 5.9 percent; HR 0.71, 95% CI 0.59-0.85, respectively). However, the rate of the primary safety end point of moderate or severe bleeding, applying the GUSTO criteria, was increased with continued DAPT (2.5 versus 1.6 percent, p = 0.001). In DAPT, the magnitude of benefit was greater for those with than those without MI [47]. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment'.)

PEGASUS-TIMI 54 randomly assigned 21,162 patients with prior MI (41 percent NSTEMI) one to three years earlier (median time 1.7 years) to one of two doses of ticagrelor (90 or 60 mg twice daily) or placebo [48]. All patients continued aspirin. The primary efficacy end point (a composite of cardiovascular death, MI, or stroke) occurred less often with ticagrelor than with placebo at three years (7.85, 7.77, and 9.04 percent, respectively; HRs 0.85, 95% CI 0.75-0.96 and 0.84, 95% CI 0.74-0.95). The rate of the primary safety end point of Thrombolysis In Myocardial Infarction major bleeding was higher in the ticagrelor 90 and 60 mg groups (2.6, 2.3, and 1.06 percent, respectively; p<0.001 for each dose versus placebo), but there was no difference in the rates of fatal and nonfatal intracranial hemorrhage (0.63, 0.71, and 0.60 percent, respectively).

Switching from ticagrelor or prasugrel to clopidogrel — Either ticagrelor or prasugrel is preferred to clopidogrel as the initial P2Y12 inhibitor in NSTEMI patients undergoing PCI. However, as many as 10 percent of patients may need to switch to clopidogrel prior to discharge, and there may be a real or perceived need to do so in similar numbers of patients after discharge [31,49,50]. Common reasons include an increased bleeding risk, non-bleeding side effects, and cost. The optimal strategy for deciding which patients might be switched, as well as when and how to switch, is not known.

Based on mechanism of action and pharmacokinetic data, we advocate the following approaches [49,51]:

For patients who have been receiving 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 [52].

For patients who have been receiving 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.

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

The above recommendations are based on knowledge of the mode of action and pharmacodynamic properties of these P2Y12 inhibitors. (See "Platelet biology and mechanism of anti-platelet drugs", section on 'ADP receptors (P2Y1 and P2Y12)'.)

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). We then give ticagrelor 90 mg twice daily beginning approximately 12 hours later.

Elderly patients — In general, increasing age is associated with increased risks of both bleeding and recurrent ischemic events. There is some evidence to suggest that clopidogrel is a reasonable alternative to ticagrelor or prasugrel in these patients for whom an early decision is made to treat with DAPT for one year.

In the POPular AGE open-label trial, 1002 patients aged 70 years or older were randomly assigned to clopidogrel or either ticagrelor (95 percent) or prasugrel (5 percent) for one year after NSTEACS [53]. Approximately 65 percent of patients underwent coronary artery revascularization. The rate of the primary outcome (bleeding requiring medical intervention) was lower with clopidogrel (18 versus 24 percent; HR 0.71, 95% CI 0.54-0.94). There were no significant differences between the two strategies in the rates of ischemic end points such as MI or cardiovascular death.

Cangrelor — Cangrelor is an intravenous P2Y12 inhibitor that has been compared with either clopidogrel or placebo in three randomized trials that included patients with NSTEACS and evaluated 48-hour outcomes. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Cangrelor'.)

Cangrelor was approved for use as an adjunct to PCI in patients who have not been treated with a P2Y12 platelet inhibitor and who are not being given a glycoprotein IIb/IIIa inhibitor. We believe it is reasonable to give cangrelor in patients with NSTEACS undergoing PCI who have not been adequately pretreated with a P2Y12 inhibitor, as it has an almost immediate antiplatelet effect. We do not use it routinely.

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".)

LABORATORY TESTING — All patients started on a P2Y12 inhibitor or a glycoprotein (GP) IIb/IIIa inhibitor should have a baseline platelet count. Patients receiving a P2Y12 inhibitor do not need routine follow-up platelet counts, whereas we obtain them after four hours and daily in patients receiving continuous GP IIb/IIIa inhibitor.

PATIENTS TAKING ORAL ANTICOAGULANTS — The use of oral anticoagulant therapy is necessary in some patients following ACS, such as those with atrial fibrillation, left ventricular mural thrombus, prosthetic heart valves, or deep vein thrombosis. In such patients, the risk of bleeding complications is increased by combination of an oral anticoagulant with dual antiplatelet therapy. The approach to antithrombotic therapy in such patients with indications for both anticoagulant and antiplatelet therapy is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Bleeding' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients", section on 'Rivaroxaban'.)

RECOMMENDATIONS OF OTHERS — Our recommendations in this topic are generally consistent with those made in major society guidelines and their focused updates [54-58].

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

Antiplatelet therapy for all patients

For all patients with non-ST-elevation acute coronary syndrome (NSTEACS), we recommend dual antiplatelet therapy with aspirin and a platelet P2Y12 inhibitor, as opposed to single antiplatelet therapy (Grade 1B). (See 'Rationale' above.)

We give aspirin at the time of diagnosis rather than later. The first aspirin tablet should be chewed and should contain 162 to 325 mg. At discharge, the dose of aspirin should be 75 to 100 mg daily; if ticagrelor is chosen as the platelet P2Y12 inhibitor, the discharge dose of aspirin should not be greater than 100 mg daily. (See 'Aspirin for all patients' above.)

The approach to the timing of initiation and choice of P2Y12 inhibitor depends on whether the patient will be treated with an invasive or an ischemia-guided approach as presented directly below.

Invasive approach

For NSTEACS patients for whom an invasive evaluation is planned, we treat with a P2Y12 inhibitor, and we recommend ticagrelor or prasugrel rather than clopidogrel (Grade 1A). (See 'Choice of drug' above.)

If diagnostic angiography and possible percutaneous coronary intervention (PCI) are performed before 24 hours (we generally attempt to perform angiography much sooner than 24 hours), we suggest waiting to start a P2Y12 inhibitor until after diagnostic angiography rather than pretreating the patient (Grade 2C). The loading doses are: ticagrelor 180 mg and prasugrel 60 mg. (See 'Dose' above and 'Timing' above.)

For patients in whom angiography will be delayed more than 24 hours, we consider administering a potent P2Y12 inhibitor as soon as the diagnosis is given or withholding it until after angiography. Both are reasonable choices. The decision to pretreat is favored in patients at high ischemic risk and low bleeding risk.

If the P2Y12 inhibitor is given before angiography, we recommend ticagrelor rather than prasugrel (Grade 1B). (See 'Timing' above.)

Most patients with NSTEACS who are scheduled for PCI do not require glycoprotein (GP) IIb/IIIa inhibitor therapy. For patients with evidence of ongoing ischemia despite therapy with aspirin plus a P2Y12 inhibitor or those at very high risk of an ischemic event or complication of PCI (such as those with a large thrombus burden seen at angiography), we suggest the addition of a GP IIb/IIIa inhibitor (Grade 2C). This is particularly true if they have not received ticagrelor or prasugrel. (See 'Invasive management' above.)

We consider tirofiban or eptifibatide reasonable choices. Cost and local practice may influence the choice of agent. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and 'Glycoprotein IIb/IIIa inhibitors' above.)

Ischemia-guided approach – For those patients managed with an ischemia-guided approach, we suggest ticagrelor rather than clopidogrel (Grade 2B), and we suggest clopidogrel rather than prasugrel (Grade 2C). (See 'Ischemia-guided management' above.)

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

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