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Oral Antiplatelet Therapy After Acute Coronary Syndrome A Review

Hassan Kamran, MD; Hani Jneid, MD; Waleed T. Kayani, MD; Salim S. Virani, MD, PhD; Glenn N. Levine, MD; Vijay Nambi, MD, PhD; Umair Khalid, MD

A

pproximately 1 million patients experience an acute coro-nary syndrome (ACS) in the United States annually, con-sisting of ST-elevation myocardial infarction (STEMI), non-STEMI, and unstable angina.1

Of these, approximately 14% do not survive the event.1

Treatment goals for patients presenting with ACS focus on symptom relief and preventing complications such as recurrent myocardial infarction (MI) or death.2

Antiplatelet therapy is the principal treatment strategy for ACS, along with timely revas-cularization when indicated.2

The most recent 2016 American Col-lege of Cardiology/American Heart Association (ACC/AHA) Focused Update on duration of dual antiplatelet therapy (DAPT) gave a class I recommendation (ie, all patients with ACS) for immediate aspirin

therapy of between 162 and 325 mg followed by maintenance aspi-rin of 81 mg daily, which is typically continued indefinitely.3

In addi-tion to aspirin, a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagre-lor) has a class I recommendation, meaning that this therapy should be prescribed with aspirin for at least 12 months, based on consis-tent clinical trial evidence.3

Since these recommendations were issued, randomized trials have evaluated new antiplatelet regimens and alternate durations of antiplatelet therapy.4

This review specifi-cally addresses DAPT for patients who are not prescribed oral anti-coagulation. Newer evidence regarding oral antiplatelet medica-tions for ACS, focusing on recent clinical trials and their clinical implications is reviewed.

the United States with an annual incidence of approximately 1 million. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces cardiovascular event rates after ACS.

Cardiology/American Heart Association (ACC/AHA) recommended aspirin plus a P2Y12 inhibitor for at least 12 months for patients with ACS. Since these recommendations were published, new randomized clinical trials have studied different regimens and durations of antiplatelet therapy. Recommendations vary according to the risk of bleeding. If bleeding risk is low, prolonged DAPT may be considered, although the optimal duration of prolonged DAPT beyond 1 year is not well established. If bleeding risk is high, shorter duration (ie, 3-6 months) of DAPT may be reasonable. A high risk of bleeding traditionally is defined as a 1-year risk of serious bleeding (either fatal or associated with aⱖ3-g/dL drop in hemoglobin) of at least 4% or a risk of an intracranial hemorrhage of at least 1%. Patients at higher risk are 65 years old or older; have low body weight (BMI <18.5), diabetes, or prior bleeding; or take oral

anticoagulants. The newest P2Y12 inhibitors, prasugrel and ticagrelor, are more potent, with high on-treatment residual platelet reactivity of about 3% vs 30% to 40% with clopidogrel and act within 30 minutes compared with 2 hours for clopidogrel. Clinicians should avoid prescribing prasugrel to patients with a history of stroke or transient ischemic attack because

of an increased risk of cerebrovascular events (6.5% vs 1.2% with clopidogrel, P = .002) and

should avoid prescribing it to patients older than 75 years or who weigh less than 60 kg. The ISAR-REACT-5 trial found that prasugrel reduced rates of death, myocardial infarction, or stroke at 1 year compared with ticagrelor among patients with ACS undergoing percutaneous

coronary intervention (9.3% vs 6.9%, P = .006) with no significant difference in bleeding.

Recent trials suggested that discontinuing aspirin rather than the P2Y12 inhibitor may be associated with better outcomes.

events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics—risk of bleeding,

Author Affiliations: Section of

Cardiology, Department of Medicine,Baylor College of Medicine, Houston,Texas (Kamran, Jneid, Kayani, Virani,Levine, Nambi, Khalid); Section ofCardiology, Department of Medicine,Michael E. DeBakey VA MedicalCenter, Houston, Texas (Jneid, Virani,Levine, Nambi, Khalid).

Corresponding Author: Umair

Khalid, MD, Michael E. DeBakey VAMedical Center and Baylor College ofMedicine, 2002 Holcombe Blvd(Mail Code: 111B), VAMC Office3C-320A, Houston, TX 77030().

Section Editor: Mary McGrae

McDermott, MD, Deputy Editor.

JAMA | Review

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We reviewed the 2016 ACC/AHA and the 2017 and 2020 European Society of Cardiology (ESC) guidelines on antiplatelet therapy for ACS.3,5,6

We reviewed studies used to support these guideline documents and screened their references for additional studies, resulting in the identification of 2 meta-analyses and 16 randomized clinical trials. We also conducted a PubMed search on

September 5, 2020, using keywords DAPT and ACS to identify

meta-analyses and randomized clinical trials published after the 2017 ESC guidelines. The PubMed search identified 26 articles. Of these, 3 meta-analyses and 4 randomized clinical trials were the only studies that evaluated DAPT selection and duration and were included. Only English-language articles reporting on adult human data were included.

Questions commonly asked by generalist clinicians are shown in the Box.

Pathophysiology of ACS

ACS predominantly results from disrupted atherosclerotic plaque leading to thrombus formation and acute obstruction of coronary

blood flow.7

Although more commonly caused by plaque rupture, ACS can also result from plaque erosion, defined as thrombus for-mation despite a plaque with an intact fibrous cap.7In up to 30% of patients, ACS occurs without significant epicardial coronary artery disease, for example in settings of coronary dissection, vasospasm, arteritis, myocardial bridging, or embolism.8

MI with nonobstructive coronary arteries (MINOCA) is another clinical diagnosis that is established after excluding other secondary causes of MI without coronary artery disease and occurs in 5% to 6% of patients with MI.9,10

A study11

involving women diagnosed with MIs showed that multimodality imaging with coronary opti-cal coherence tomography and cardiac magnetic resonance imaging identified the mechanism of MINOCA in 84.5% of the women, three-quarters of which were found to be ischemic. Sev-eral elements determine plaque stability and degree of myocar-dial injury. Unstable plaques, which have higher rates of rupture and risk of ACS, have thin fibrous caps with large lipid cores.12 Plaque disruption exposes thrombogenic material within the plaque, such as von Willebrand factor, resulting in platelet adhesion.10

In response to potent agonists such as thrombin or collagen, platelets release adenosine diphosphate,10

which acti-vates the platelet P2Y12 receptor, which actiacti-vates the glycopro-tein IIb/IIIa receptor, leading to platelet aggregation and eventual thrombus formation.13

A goal of medical therapy for ACS is pre-venting platelet activation and aggregation (Figure).

Antiplatelet therapy is especially important after percutane-ous coronary intervention (PCI) because balloon angioplasty and stenting stretch the coronary arterial wall, disrupting endothe-lium and exposing subendothelial collagen.12

Inflammation result-ing from this process activates platelets and increases the pro-pensity for stent thrombosis.14

Over time, this inflammation can lead to proliferation and migration of smooth muscle cells in the media and intima, causing in-stent restenosis.14,15

This commonly occurs with bare-metal stents, for which in-stent restenosis rates range from 17% to 41%.14

In contrast, drug-eluting stents are coated with a polymer that elutes antineoplastic drugs, such as sirolimus, zotarolimus, or everolimus, to inhibit smooth muscle cell proliferation and decrease restenosis.16

However, drug-eluting stents are associated with delayed vessel healing and pro-longed time to endothelialization of the stent, increasing risk of later stent thrombosis that may require patients to take DAPT for longer periods.17

Second-generation and newer drug-eluting stents are thinner with more biocompatible polymers, such as poly(lactide-co-glycide) and poly(vinylidene fluoride-co-hexafluoropropylene). These newer polymers minimize inflam-mation and stent thrombosis.16

Late (between 1 to 12 months) and very late (after 12 months) stent thrombosis were more com-mon with first-generation drug-eluting stents than bare-metal stents with 3-year follow-up rates of 2.2% vs 1.5%, respectively.18 Second-generation drug-eluting stents have rates of stent throm-bosis that are comparable with those of bare-metal stent, if not better.18

The type of stent therefore significantly influences opti-mal DAPT duration.

Aspirin irreversibly inhibits platelet activation by blocking thromboxane A2synthesis.19

The beneficial effects of aspirin in treating ACS have been well established since the 1980s.19 Box. Common Questions Asked by Internists Regarding Oral

Antiplatelet Therapy After Acute Coronary Syndrome

Should NSAIDs be used concomitantly with aspirin?

Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antiplatelet efficacy of aspirin due to their cyclooxygenase 1 (COX-1) inhibition. It is for this reason that NSAIDs (particularly ibuprofen) should ideally be avoided by these patients.

Is it safe to hold antiplatelet medications prior to surgeryin a patient with history of acute coronary syndrome?

It is best to consider the bleeding risk of the surgery against the ischemic risk of holding antiplatelet medications. In general, aspirin should be continued without any interruption, including on the day of the surgery, unless the bleeding risk is prohibitive (eg, neurosurgery). As for the P2Y12 inhibitor, if the most recent acute coronary syndrome (ACS) episode or stent placement is longer than 6 to 12 months, most physicians are comfortable holding it for 5 days prior to surgery. If this period is less than 6 months, expert consultation with the interventional cardiologist is recommended.

Which patients have a high risk of bleeding and should typicallyreceive dual antiplatelet therapy for less than 12 months? Patients with advanced age (>65 years old), low body weight, diabetes, prior bleeding, or taking oral anticoagulants are considered higher risk. Dual antiplatelet therapy (DAPT) score and expert cardiology consultation can further inform clinical decision making.

When is it reasonable to extend the DAPT duration for longerthan 12 months?

Extended duration DAPT (ie, > 12 months) may be considered for patients with low bleeding risk and high ischemic risk, such as those with multiple prior ACS episodes, diabetes, and heart failure.

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Figure. Antiplatelet Medications for Acute Coronary Syndrome

1Plaque rupture or erosion

Drug administration type

Binds to P2Y12 receptor and inhibits adenosine

Binds to glycoprotein IIb/IIIa (GpIIb/IIIa) receptor and receptor (PAR)-1 and inhibits thrombin induced platelet activation

VorapaxorCangrelor

Aspirin reversibly inhibits platelet activation by inhibiting the cyclooxygenase-1enzyme and blocking TXA2synthesis. The P2Y12 receptor inhibitors block ADPactivation of the platelet. The P2Y12 receptor is required for G12

protein–mediated activation of the GpIIb/IIIa receptor. This results in decreasedplatelet degranulation and aggregation. Clopidogrel requires a 2-stepmetabolism by hepatic cytochrome enzymes for biotransformation to its activeform, whereas prasugrel undergoes a single-step conversion to its activemetabolite. Ticagrelor and cangrelor are direct-acting reversible antagonists

of the P2Y12 receptor. Abciximab, eptifibatide, and tirofiban are directinhibitors of the GpIIb/IIIa receptors and thereby inhibit platelet aggregation.Vorapaxar is an oral protease–activated receptor (PAR)–1 antagonist thatinhibits thrombin-induced platelet activation by reversible binding of the PAR-1receptor on platelets. Cangrelor, abciximab, eptifibatide, and tirofiban areintravenous antiplatelet medications. Because these are often used togetherwith an oral antiplatelet regimen for treating acute coronary syndrome, they areincluded in the figure.

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ISIS-2 (Second International Study of Infarct Survival),20 a ran-domized clinical trial, demonstrated that patients with suspected MI taking 160 mg of aspirin daily for 5 weeks had reduced total vascular mortality by 23% compared with placebo (9.4% vs

11.8%, P < .001). A meta-analysis of 287 studies involving

135 000 patients with acute or previous vascular disease or another predisposing condition such as diabetes demonstrated that aspirin use was associated with a 23% reduction in major cardiovascular events (12.9% with aspirin vs 16% without) and a 33% reduction in nonfatal MI (2.45% with aspirin vs 3.66% without).21

Unless there are contraindications, such as risk of life-threatening bleeding or hypersensitivity, all patients with ACS should start aspirin therapy with a load of between 162 mg and 325 mg followed by maintenance of 81 mg daily according to cur-rent guidelines.

P2Y12 Receptor Inhibitors

P2Y12 receptor inhibitors consist of clopidogrel, prasugrel, and ti-cagrelor and are often combined with aspirin for DAPT after ACS. (Table 1, Table 2, and Table 3). Adenosine diphosphate activation of the platelet P2Y12 receptor results in G12-mediated activation of the glycoprotein IIb/IIIa receptor.37

Inhibiting the P2Y12 receptor de-creases platelet degranulation and aggregation.37

Clopidogrel, a thienopyridine, requires 2-step metabolism for bio-transformation to its active form. The cytochrome P450 enzyme mediates oxidation of clopidogrel to 2-oxoclopidogrel, followed by conversion of 2-oxoclopidogrel to an active metabolite that irreversibly inhibits the P2Y12 receptor on the platelet surface.38 A 600-mg dose of clopidogrel achieves maximal inhibition of the P2Y12 receptor within 2 to 4 hours.39

In the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial,24

patients with non-STEMI treated with 75 mg to 325 mg daily aspirin were randomized to clopidogrel (300 mg immediately, followed by 75 mg once daily; 6259 patients) or placebo (6303 patients). At 12 months, the primary composite outcome of death from cardio-vascular causes, nonfatal MI, or stroke was significantly lower in the clopidogrel group than in the placebo group (9.3% vs 11.4%,

P < .001) with increased major bleeding (3.7% vs 2.7%, P = .001),

but no increase in fatal bleeding or intracranial hemorrhage. Reduction in the primary outcome was primarily due to nonfatal MI (5.2% vs 6.7%, relative risk [RR], 0.77; 95% CI, 0.67-0.89). A subgroup analysis involving the 2658 patients who received PCI showed that clopidogrel was associated with significantly lower rates of cardiovascular death, MI, or urgent target-vessel revascu-larization within 30 days of PCI than was placebo (4.5% vs 6.4%;

RR, 0.7; CI, 0.50-0.97, P = .03).36

The CURRENT–OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events–Organization to Assess Strate-gies in Ischemic Syndromes) trial23

investigated optimal clopido-grel dosing. This trial randomized 25 086 patients with ACS to receive either standard-dose clopidogrel (300-mg loading dose, then 75 mg daily) or high-dose clopidogrel (300-mg loading dose, 150 mg daily for 6 days, then 75 mg daily). High-dose clopidogrel did not reduce the primary composite end point of cardiovascular mortality, stroke, or MI at 30 days compared with standard-dose

clopidogrel (4.2% vs 4.4%; HR, 0.94; 95% CI, 0.83-1.06; P = .30)

but was associated with higher rates of major bleeding (2.5% vs

2.0%; HR, 1.24; 95% CI, 1.05-1.46; P = .01).

Like clopidogrel, prasugrel is a thienopyridine but has a faster onset of action, acting within 30 to 60 minutes.39

Prasugrel is hydrolyzed by intestinal esterases to a thiolactone intermediate that is acti-vated by a cytochrome P450-dependent step to form the active metabolite R-138727. This active metabolite binds irreversibly to the P2Y12 receptor to inhibit platelet activation and aggregation.40 The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction) study,30

randomized 13 608 patients presenting with ACS for whom PCI was planned to receive either prasugrel (60-mg loading dose, then 10-mg daily mainte-nance dose) or clopidogrel (300-mg loading dose, then 75 mg daily maintenance dose) for a median of 14.5 months. The primary com-posite outcome of cardiovascular mortality, nonfatal MI, or nonfatal stroke was significantly reduced in those treated with prasugrel compared with clopidogrel (9.9% vs 12.1%; hazard ratio [HR], 0.81;

95% CI, 0.73-0.90; P < .001), primarily due to a reduction in MI.

Major bleeding was increased in participants who received

prasug-rel (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03-1.68; P = .03). In post hoc

analysis, there was increased fatal bleeding rates in patients 75 years or older (1.0% vs 0.1%), increased major or minor bleeding in patients weighing less than 60 kg (10.1% vs 6.5%), and a statisti-cally significant increase in stroke in patients with a history of

stroke or transient ischemic attack (TIA) (6.5% vs 1.2%, P = .002).

Overall, there was no benefit for patients 75 years or older or for those weighing less than 60 kg, and there was net harm to patients with a history of TIA or stroke. When the US Food and Drug Admin-istration (FDA) approved prasugrel in July 2009, it prohibited pre-scribing it to patients with a history of stroke or TIA.41

The TRILOGY-ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial31compared 10 mg of prasugrel with 75 mg of clopidogrel in 9326 patients with non–STEMI who were selected for medical management without revascularization. At 30 months, the primary composite end point of cardiovascular death, MI, or stroke among patients younger than 75 years did not significantly differ between the groups (13.9% with prasugrel vs 16.0% with clopidogrel; HR,

0.91; 95% CI, 0.79-1.05; P = .21). Patients 75 years or older or

weighing less than 60 kg received a lower dose of prasugrel (5 mg daily) based on previous pharmacokinetic modeling that showed that patients weighing less than 60 kg who received 5 mg of prasu-grel resulted in a similar antiplatelet effect to that of 10 mg daily in patients weighing more than 60 kg.42

TIMI major bleeding did not differ between maintenance low-dose prasugrel and clopidogrel among patients older than 75 years (4.1% vs 3.4%; HR, 1.09; 95%

CI, 0.57-2.08, P = .79).43

The ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial32

demon-strated that pretreatment with prasugrel compared with placebo did not reduce the rates of major ischemic events at 30 days among patients with non-STEMI undergoing coronary angiography

(10.8% vs 10.8%, P = .98) but it increased TIMI major or minorbleeding (3.6% vs 1.2%, P < .001). Based on results from these 2

trials, prasugrel should be considered after PCI is selected as the

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Table 1. Major Studies of Oral Antiplatelet Agents in Acute Coronary Syndrome Abbreviations: ACCOAST, A Comparison of Prasugrel at PCI or Time of Diagnosis

of Non–ST-Elevation Myocardial Infarction; ACS, acute coronary syndrome;CAPRIE, Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events;CLARITY-TIMI, Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis inMyocardial Infarction; CREDO, Clopidogrel for Reduction of Events DuringObservation; CURE, Clopidogrel in Unstable Angina to Prevent RecurrentEvents; Current–OASIS 7, Clopidogrel Optimal Loading Dose Usage to ReduceRecurrent Events–Organization to Assess Strategies in Ischemic Syndromes;GpIIb/IIIc, glycoprotein IIB/IIIa; CV, cardiovascular; HR, hazard ratio;

ISAR-REACT-5, Intracoronary Stenting and Antithrombotic Regimen: Rapid EarlyAction for Coronary Treatment 5; ISIS-2, Second International Study of Infarctsurvival; MI, myocardial infarction; NSTEMI, non–ST-elevation myocardialinfarction; PAD, peripheral artery disease; PCI, percutaneous coronary

intervention; PEGASUS, Prevention of Cardiovascular Events in Patients withPrior Heart Attack Using Ticagrelor Compared to Placebo on a Background ofAspirin; PLATO, Study of Platelet Inhibition and Patient Outcomes; STEMI,ST-elevation myocardial infarction; TRACER, Thrombin-Receptor AntagonistVorapaxar in Acute Coronary Syndromes; TRA 2P, Thrombin ReceptorAntagonist in Secondary Prevention of Atherothrombotic Ischemic Events;TRILOGY-ACS, Targeted Platelet Inhibition to Clarify the Optimal Strategy toMedically Manage Acute Coronary Syndromes; TRITON, Trial to AssessImprovement in Therapeutic Outcomes by Optimizing Platelet Inhibition withPrasugrel; UA, unstable angina.

aThe point estimate is reported as a relative risk.

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treatment strategy. In addition, prasugrel is generally not recom-mended for patients with ACS who are older than 75 years or weigh less than 60 kg because no net clinical benefit was seen for these groups. A 5-mg daily maintenance dose can be considered for patients weighing less than 60 kg if prasugrel is used.

Unlike clopidogrel and prasugrel, ticagrelor is not a thienopyridine. Ticagrelor is a direct-acting reversible antagonist of the P2Y12 receptor. It is associated with faster onset (peak activity within 30 minutes) and shorter half-life (8-12 hours) than clopidogrel.44 Ticagrelor-induced nonexertional dyspnea occurs in 10% to 20% of patients and is thought to be related to ticagrelor-induced eleva-tions in plasma adenosine levels.45

In many patients, ticagrelor-related dyspnea improves within the first week of treatment and only approximately 4% of patients discontinue ticagrelor for this adverse effect.45

The PLATO (Study of Platelet Inhibition and Patient Outcomes) trial46

randomized 18 624 patients admitted for ACS to receive either ticagrelor (180-mg loading dose, then 90 mg twice daily) or clopidogrel (300-600 mg loading dose, then 75 mg daily). The primary composite outcome was cardiovascular mortal-ity, stroke, or MI. At 12 months’ follow-up, ticagrelor was associated with a significant reduction in the primary outcome compared with

clopidogrel (9.8% vs 11.7%; HR, 0.84; 95% CI, 0.77-0.92, P < .001),

primarily due to reductions in MI and cardiovascular death. Ticagre-lor was also associated with a significant reduction in all-cause

mor-tality (4.5% vs 5.9%; HR, 0.78; 95% CI, 0.69-0.89; P < .001).28 Major bleeding that was not related to coronary artery bypass graft

surgery was higher in the ticagrelor group (4.5% vs 3.8%, P = .03).

Prespecified analysis of PLATO showed that the efficacy of ticagrelor appeared attenuated in those treated with higher doses of aspirin. The HR of primary composite outcome for ticagrelor vs clopidogrel was 1.45 (95% CI, 1.01-2.09) for patients treated with aspirin doses of 300 mg or more and 0.77 (95% CI, 0.69-0.86) for those treated with aspirin doses 100 mg or less.47

As a result, FDA approval of ticagrelor for ACS was accompanied by a warning to avoid maintenance daily aspirin doses of more than 100 mg when using ticagrelor.48

Prasugrel vs Ticagrelor

The 2016 ACC/AHA guidelines give a class IIA recommendation (ie, indicating that this treatment is reasonable) for prescription of

either ticagrelor or prasugrel over clopidogrel for patients with ACS who were not at high risk of bleeding.3

In the TRITON-TIMI 38 trial,30

prasugrel was only administered to patients referred for PCI. The ACCOAST trial showed no benefit of prasugrel treatment prior to coronary angiography when examining the composite end point of death from cardiovascular causes, MI, stroke, urgent revascular-ization, or glycoprotein IIb/IIIa inhibitor rescue therapy (HR with pretreatment vs no pretreatment, 1.02; 95% CI, 0.84-1.25;

P = .81).32

In contrast, ticagrelor was prescribed to all patients with ACS in the PLATO trial (including noninvasive and invasive treat-ment strategies).28

The 2016 AHA/ACC guidelines and the FDA package label do not recommend prasugrel as an option for DAPT unless PCI is planned.3,41

The ISAR-REACT-5 (Intracoronary Stenting and Antithrom-botic Regimen: Rapid Early Action for Coronary Treatment 5) study33 was the first randomized trial to compare ticagrelor with prasugrel. Patients with ACS undergoing invasive therapy were randomized to receive ticagrelor (n = 2012) or prasugrel (n = 2006) and were fol-lowed up for 1 year. Patients with history of stroke, TIA, or intracra-nial hemorrhage were excluded. Patients older than 75 years or who weighed less than 60 kg received a daily maintenance dose of 5 mg of prasugrel. Prasugrel was superior to ticagrelor in this trial. The pri-mary outcome of death, MI, or stroke at 1 year occurred in 9.3% of the ticagrelor group compared with 6.9% of the prasugrel group

(P = .006) with no significant difference in bleeding. However, this

trial had an open-label design, and in the intention-to-treat analy-sis, 32.5% of patients in the ticagrelor group and 30.4% of patients in the prasugrel group were not treated with the assigned drug. Given inconsistency of results and the smaller sample size compared with previous trials, a definitive statement of superiority of prasugrel com-pared with ticagrelor cannot be made at this time. However, the 2020 ESC-ACS guidelines6

gave a class IIa recommendation that pra-sugrel be preferentially prescribed over ticagrelor for patients with non-STEMI undergoing PCI.

Vorapaxar is an oral protease-activated receptor (PAR)–1 antago-nist that inhibits thrombin-induced platelet activation by revers-ible binding of the PAR-1 receptor on platelets.34

In the TRACER (Thrombin-Receptor Antagonist Vorapaxar in ACSs) trial,34

vora-paxar was compared with placebo when added to standard medi-cal therapy including DAPT in 12 944 patients with non-STEMI. The Table 2. Mechanism of Action and Dosing of Oral Antiplatelet Agents

US Food and Drug

Mechanism of actionCyclooxygenase

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primary composite outcome was cardiovascular mortality, MI, stroke, recurrent ischemia, or urgent revascularization. Vorapaxar did not significantly reduce the primary outcome (18.5% vs 19.9% in the

pla-cebo group, P = .07), and significantly increased the risk of TIMI ma-jor bleeding (3.2% vs 2.1% in placebo, P < .001). In the TRA 2P–TIMI

50 (Vorapaxar in the Secondary Prevention of Atherothrombotic Events) trial,35

adding vorapaxar to standard medical therapy in-cluding DAPT for patients with a history of MI, ischemic stroke, or peripheral artery disease reduced the incidence of cardiovascular

death (9.3% vs 10.5%, P < .001) with increased rates of clinically sig-nificant bleeding (15.8% vs 11.1%, P < .001). In a subanalysis of TRA2

P-TIMI 50 original study of patients with lower extremity periph-eral artery disease, vorapaxar reduced rates of hospitalization for

acute limb ischemia (2.3% vs 3.9%, P = .006) and peripheral ar-tery revascularization (18.4% vs 22.2%, P = .02), compared with pla-cebo but with increased bleeding (7.4% vs 4.5%; P = .001).49

Based on the small clinical benefit and increased risk of bleeding, vora-paxar has not been widely adopted in clinical practice.

Duration of Antiplatelet Therapy

Randomized clinical trials have studied varying durations of DAPT after PCI to identify optimal therapy duration.50

Bittl et al51 pooled data from 11 randomized clinical trials of 33 051 patients with coro-nary artery disease who predominantly received the newer genera-tion drug-eluting stent. Compared with 3 to 6 months of DAPT, 12 months of DAPT was associated with no difference in all-cause mor-tality (1.32% vs 1.12%, OR, 1.17; 95% CI, 0.85-1.63), major hemor-rhage (0.61% vs 0.37%, OR, 1.65; 95% CI, 0.97-2.82), MI (1.35% vs 1.54%, OR, 0.87; 95% CI, 0.65-1.18), or stent thrombosis (0.38% vs 0.46%, OR, 0.87; 95% CI, 0.49-1.55). Compared with 6 to 12 months of DAPT, 18 to 48 months of DAPT was associated with no differ-ence in all-cause mortality (2.12% vs 1.84%, OR, 1.14; 95% CI, 0.92-1.42) but was associated with lower rates of MI (1.58% vs 2.73%, OR, 0.67; 95% CI, 0.47-0.95), and stent thrombosis (0.35% vs 0.94%, OR, 0.45; 95% CI, 0.24-0.74). However, compared with 6 to 12 months of DAPT, 18 to 48 months was also associated with in-creased major bleeding (1.80% vs 1.12%, OR, 1.58; 95% CI, 1.20-2.09). Prolonged DAPT of 18 to 48 months was associated with 3 fewer stent thromboses, 6 fewer MIs, and 5 more major bleeding episodes per 1000 patients. Eight of the 11 trials included in the re-view enrolled lower-risk patients. Therefore, results may not be ap-plicable to high-risk patients. In the 3 trials of high-risk patients with MI, DAPT use for longer than 1 year was associated with reduced risk of cardiovascular death, MI, and stroke (7.77% vs 9.04%, HR, 0.84; 95% CI, 0.74-0.95) but increased major bleeding (2.30% vs 1.06%, HR, 2.32; 95% CI, 1.68-3.21). The 2016 ACC/AHA guidelines gave a class I recommendation indicating that all patients with PCI for ACS should be treated with DAPT, consisting of aspirin with either clopi-dogrel, prasugrel, or ticagrelor, for at least 12 months. These guide-lines also gave a class IIb recommendation, indicating that early dis-continuation of antiplatelet therapy may be considered after 6 months if bleeding risk is high and that antiplatelet therapy should be continued for more than 12 months if bleeding risk is low.3

Pa-tients with prior bleeding during DAPT or while taking oral antico-agulants are considered at high risk of bleeding. Additional factors such as advanced age (>65 years), low body weight, diabetes, or chronic kidney disease also increase bleeding risk. However, fac-tors such as advanced age and diabetes increase both bleeding and

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ischemic risks, making the determination of optimal DAPT dura-tion more difficult. Although assessment of bleeding risk is often a clinical judgment, there are tools such as the DAPT score that can help guide decisions about whether to continue DAPT beyond 12 months.52

The score incorporates factors such as age, diabetes, cur-rent cigarette use, prior PCI or MI, heart failure, MI at presentation, vein graft PCI, and stent diameter smaller than 3 mm. This risk score is a numerical value between −2 and 9 whereby high scores (ⱖ2) fa-vor prolonged DAPT duration while low scores fafa-vor discontinua-tion of DAPT at 12 months.

A 2017 meta-analysis53

of 6 randomized trials comparing short-term DAPT (<6 months) with long-short-term DAPT (1 year) after place-ment of drug-eluting stents reported that for patients with ACS, short-term DAPT was associated with higher rates of ischemic events than was long-term DAPT.

A 2019 meta-analysis,4

involving 21 457 patients, 7325 of whom with ACS, assessed the benefit of increasing DAPT for more than a year after placement of drug-eluting stents. The study found that DAPT for 1 year or less was associated with higher rates of MI (2.7% vs 1.6%; HR, 1.63; 95% CI, 1.37-1.95) and lower rates of bleeding (0.6% vs 0.9%; HR, 0.64; 95% CI, 0.42-0.99) than DAPT for longer than a year. The study reported a net clinical benefit, defined as the com-posite of MI and major bleeding, of prolonged DAPT for patients with ACS (4.3% in shorter vs 2.7% in longer DAPT; HR, 1.59; 95% CI, 1.24– 2.02) but not among those with stable coronary artery disease.

In summary, randomized clinical trials suggested benefit for 12 months of DAPT for patients with ACS. Patients with low risk of bleed-ing as determined by clinical judgement or by risk assessment tools such as the DAPT risk score may be treated for longer durations. Shorter duration of DAPT may be appropriate for PCI in the setting of stable angina.

Short-term DAPT Followed by P2Y12 Inhibitor Monotherapy After PCI

Among patients treated with DAPT after PCI, recent trials have tested whether stopping aspirin instead of the P2Y12 inhibitor improved outcomes. The STOPDAPT-2 (Short and Optimal Duration of Dual An-tiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2) trial54

evaluated 1 month of DAPT with aspirin and clopi-dogrel followed by clopiclopi-dogrel monotherapy vs 12 months of DAPT in patients undergoing PCI for stable and unstable coronary artery disease. One month of DAPT followed by clopidogrel mono-therapy reduced the primary outcome of death, MI, stent throm-bosis, stroke, and TIMI major and minor bleeding at 1 year (2.4% vs

3.7%, P for superiority = .04). This remained statistically

signifi-cant when bleeding was removed from the composite outcome. Defi-nite or probable stent thrombosis was 0.3% in the 1-month DAPT

group compared with 0.07% in the 12-month DAPT group (P = .21).

The STOPDAPT-2 trial included a low-risk population with 62% hav-ing stable coronary artery disease.

The TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Pa-tients After Coronary Intervention) trial55

assessed DAPT of 3 months followed by ticagrelor alone compared with 12 months of DAPT among high-risk patients undergoing PCI. A total of 3555 patients, including 64% with unstable angina or non-STEMI, were ized to the short duration group and 3564 patients were random-ized to the standard group. After a mean of 12 months, the short-duration group was noninferior for the secondary outcomes of

all-cause mortality, stroke, or MI (3.9% vs 3.9%; HR, 0.99; 95% CI,

0.78-1.25, P < .001 for noninferiority) and there was a significant decrease

in the primary outcome of the Bleeding Academic Research Consor-tium (BARC) 2, 3, or 5 bleeding severity in the short-term DAPT group

(4.0% vs 7.1%, HR, 0.56; 95% CI, 0.45-0.68; P < .001 for

superior-ity). In the subset of patients with ACS, the results were the same. The TICO (Ticagrelor With or Without Aspirin in Acute Coro-nary Syndrome After PCI) trial56

evaluated ticagrelor monotherapy after 3 months of DAPT compared with 12 months of DAPT after PCI for patients with ACS receiving a bioresorbable polymer sirolimus-eluting stent. A total of 3056 patients were randomized 1:1 and were followed up for a mean of 12 months. The 3-month DAPT therapy reduced the primary outcome of net adverse clinical events (death, MI, stent thrombosis, stroke, target-vessel revascu-larization, or TIMI major bleeding) compared with standard therapy

(3.9% vs 5.9%, P = .01). This was primarily due to a reduction inmajor bleeding in the 3-month DAPT group (1.7% vs 3.0%, P = .02)

without a difference in major adverse cardiac and cerebrovascular

events (2.3% vs 3.4%, P = .09). A meta-analysis57

of 5 randomized trials studying P2Y12 inhibitor monotherapy after short-term DAPT of 1 to 3 months demonstrated that this strategy was associated with a 40% reduction in major bleeding (1.97% vs 3.13%; HR, 0.60;

95% CI, 0.45-0.79; P < .001) without an associated increase in

major adverse cardiovascular events (2.73% vs 3.11%; HR, 0.88;

95% CI, 0.77-1.02; P = .09), MI (1.08% vs 1.27%; HR, 0.85; CI, 0.69-1.06; P = .14), or death (1.25% vs 1.47%; HR, 0.85; CI, 0.70-1.03;P = .09) compared with standard 12 months of DAPT. These

find-ings were consistent in the subset of patients who underwent PCI for ACS. Together, these studies suggest that discontinuing aspirin after DAPT and continuing the P2Y12 inhibitor may be associated with better outcomes in patients with ACS. The 2020 ESC-ACS guidelines recommended that DAPT with aspirin and ticagrelor for 3 months followed by ticagrelor monotherapy should be considered for patients with non-STEMI after PCI at low risk of bleeding (class IIB recommendation).6

There is also a class IIa rec-ommendation from the 2020 ESC-ACS guidelines that DAPT with aspirin and clopidogrel for 1 month followed by clopidogrel mono-therapy should be considered for patients with non-STEMI after PCI at very high risk of bleeding.6

Very high risk of bleeding is

defined as recent bleeding in the past month or a planned surgery that cannot be delayed.3,6

Resistance to Antiplatelet Agents

Aspirin resistance is associated with genotype variation in cyclooxy-genase 1 (COX-1). A specific COX-1 haplotype present in 12% of the population has been associated with a decrease in arachidonic acid-induced platelet aggregation and thromboxane B2generation. This haplotype is associated with increased bleeding risk and with de-creased effect of aspirin.58

Another study evaluated the associa-tion of low-dose enteric coated aspirin with COX-1 inhibiassocia-tion and noted that decreased drug response on regression analysis in pa-tients who were younger or who had a higher body mass index and those with a history of prior MI.59

Concurrent use of nonsteroidal anti-inflammatory drugs, especially ibuprofen, may inhibit the an-tiplatelet effect of aspirin due to COX-1 inhibition.58

Clopidogrel resistance results from genetic variants that re-duce metabolism and activation of the drug.60

Clopidogrel is a pro-drug and requires a 2-step process for biotransformation to its active

</div>Trang 9<div class="page_container" data-page="9">

metabolite. This is mediated by several hepatic CYP450 isoen-zymes. The CYP2C19 isoenzyme is responsible for a significant part of the first step. Several genetic polymorphisms of this isoenzyme that are associated with loss of function have been described.61

Ob-servational data suggest that the presence of 1 or more of these non-functioning alleles is associated with an increased risk of adverse car-diovascular events.61

There is no evidence that genetic testing to screen these patients improves outcomes.61-63

Prasugrel is also a prodrug but no genetic factors associated with prasugrel resistance have been identified. Ticagrelor is a direct act-ing inhibitor of P2Y12 receptor and does not require conversion to an active metabolite.64,65

Clinical Implications

When determining type and duration of DAPT, clinicians should con-sult with the patient’s interventional cardiologist. For patients with ACS, dual antiplatelet therapy should be prescribed for at least 12 months unless the bleeding risk is determined to be high, in which case, at least 1 of the antiplatelet therapies could be stopped ear-lier. For example benefits of 12 months of dual antiplatelet therapy may not outweigh risks in people taking concomitant oral antico-agulant therapy, those older than 65 years, or those with a history of major bleeding. Extended duration DAPT (ie, beyond 12 months)

may be considered for patients at particularly high risk of ischemic events, such as those with multiple ACS episodes, diabetes, and heart failure. Patients with history of ACS should be treated with at least 1 antiplatelet medication for the remainder of their lifetime, unless there is a contraindication, such as a major bleeding episode.3

Al-though clinical adjudication of ischemic vs bleeding risk is impor-tant, risk-assessment tools, such as the DAPT risk score, can be help-ful when making decisions about DAPT duration.52

This review has several limitations. First, current evidence regard-ing antiplatelet therapy for acute coronary syndrome is limited by the characteristics and quality of published high-quality evidence. Second, due to the volume of evidence, not all high-quality trials could be included in this review.

Dual antiplatelet therapy reduces rates of cardiovascular events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics—risk of bleeding, myocardial ischemia.

ARTICLE INFORMATION

Accepted for Publication: January 19, 2021.Correction: This article was corrected on June 13,

2021, to amend aspirin’s role in irreversiblyinhibiting platelet activation and to changereference 19.

Author Contributions: Dr Khalid had full access to

all of the data in the study and takes responsibilityfor the integrity of the data and the accuracy of thedata analysis.

Concept and design: Kamran, Jneid, Virani, Nambi,

Acquisition, analysis, or interpretation of data:

Kamran, Kayani, Levine.

Drafting of the manuscript: Kamran, Kayani, Khalid.Critical revision of the manuscript for importantintellectual content: Kamran, Jneid, Kayani, Virani,

Levine, Nambi.

Administrative, technical, or material support:

Supervision: Jneid, Kayani, Virani, Khalid.Other - focus and presentation of data: Levine.

Conflict of Interest Disclosures: Dr Virani reported

receiving research grants from the Department ofVeterans Affairs, World Heart Federation, and theTahir and Jooma Family and honorarium from theAmerican College of Cardiology for serving as anassociate editor for the Innovations section of theACC.org editorial board; and serving on the steeringcommittee of the Patient and Provider Assessmentof Lipid Management (PALM). Dr Nambi reportedreceiving a research grant from the Department ofVeterans Affairs; being a site primary investigatorfor studies sponsored by Merck, Amgen; receivingpersonal fees from Dynamed; and having a patentpending along with Roche and Baylor College ofMedicine for the use of biomarkers in prediction ofheart failure. No other disclosures were reported.

Submissions: We encourage authors to submit

papers for consideration as a Review. Please

contact Mary McGrae McDermott, MD, at

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