Cardiovascular Insights for Primary Care Physicians

The Use of Dual Antiplatelet Therapy in High-Risk Patients With Acute Coronary Syndromes

Robert M. Guthrie, MD

The Ohio State University, Columbus, Ohio, USA

Acknowledgments

Medical writing support was provided by Alex Mellors, Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. The opinions, conclusions, and interpretation of the data and/or literature are the responsibility of the author.

Disclosures

Robert M. Guthrie MD, serves as an advisor and on the speakers’ bureaus for Janssen Pharmaceuticals, the Lilly/Boehringer/Ingelheim Partnership, AstraZeneca Pharmaceuticals, Relypsa Pharmaceuticals, and Informa (where he is the Editor-in-Chief of The Physician and SportsMedicine).

Introduction

Atherothrombosis is often the first clinical manifestation of atherosclerosis and the major cause of acute coronary syndromes (ACS) and cardiovascular death^1,2(Figure 1). As thrombotic events are platelet-driven, antiplatelet agents play a pivotal role in thrombotic cardiovascular event prevention,³ particularly in secondary prevention in high-risk patients with ACS⁴ (Table 1). ACS comprises a number of clinical manifestations, the most common being unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI).⁵

Figure 1. Clinical Manifestations of Atherothrombosis

Abbreviations: CAD, coronary artery disease; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischemic attack; VSMC, vascular smooth muscle cells.

Adapted from Meadows et al 2007⁴⁶ and Rodriguez et al 2007.⁴⁷

Table 1. Criteria For High-risk Patients¹⁰

Primary criteria:

1. Relevant rise or fall in troponin

2. Dynamic ST- or T-wave changes (symptomatic or silent)

3. Global Registry of Acute Coronary Events (GRACE) score >140

Secondary criteria:

4. Diabetes mellitus

5. Renal insufficiency (estimated glomerular filtration rate <60 mL/min/1.73 m²)

6. Reduced left ventricular function (ejection fraction <40%)

7. Early post-infarction angina

8. Recent PCI

9. Prior CABG

10. Intermediate to high GRACE score (109–140)

Abbreviations: CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.

Current international treatment guidelines for the management of patients with non-ST-segment elevation ACS (NSTE-ACS) and STEMI differ in their specific treatment recommendations (Table 2).The majority of guidelines recommend that dual antiplatelet therapy with a P2Y₁₂ receptor antagonist and low-dose aspirin be initiated as soon as possible after the acute cardiovascular event and continued for up to 12 months.^6-11 However, the optimal antiplatelet strategy, including the duration of dual antiplatelet therapy and the choice of P2Y₁₂receptor antagonist, is often unclear.⁴

Table 2. Summary of Current Guideline Recommendations for Patients With Acute Coronary Syndromes

Guideline	Recommendation
2011 ESC guideline for the management of patients with NSTE-ACS⁶	Long-term use of aspirin is recommended in all patients without contraindications A P2Y₁₂ inhibitor should be added to aspirin as soon as possible and maintained over 12 months in all patients without contraindications: Ticagrelor in patients at moderate to high risk of ischemic events, including those pre-treated with clopidogrel Prasugrel in P2Y₁₂ inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI (unless there is a high risk of life-threatening bleeding or other contraindications) Clopidogrel in patients who cannot receive ticagrelor or prasugrel
2012 ESC guideline for the management of acute STEMI⁹	Aspirin is indicated indefinitely after STEMI. Clopidogrel is indicated as an alternative in patients who are intolerant to aspirin Dual antiplatelet therapy with aspirin and either prasugrel or ticagrelor is recommended in patients treated with PCI for up to 12 months after STEMI (and for a minimum of 1 month in patients receiving BMS, and a minimum of 6 months in patients receiving DES)
2013 ACCF/AHA guideline for the management of STEMI⁸	In patients undergoing primary PCI, a loading dose of aspirin should be administered before the procedure, and a daily maintenance dose should be continued indefinitely A loading dose of a P2Y₁₂ inhibitor (clopidogrel, prasugrel, or ticagrelor) should be given as early as possible or at time of primary PCI, and a maintenance dose should be given for at least 12 months to patients receiving a BMS or DES In patients receiving fibrinolytic therapy, aspirin should be continued indefinitely, and clopidogrel should be administered for >14 days and ≤12 months
2014 AHA/ACC guideline for the management of patients with NSTE-ACS¹¹	Aspirin should be administered as soon as possible after presentation and continued indefinitely. Clopidogrel may be used as an alternative in patients unable to take aspirin Dual antiplatelet therapy with aspirin and either clopidogrel or ticagrelor is recommended for up to 12 months in patients without contraindications and treated with early invasive or ischemia-guided strategy. (Ticagrelor should be used in preference to clopidogrel) Dual antiplatelet therapy with aspirin and clopidogrel, prasugrel, or ticagrelor should be continued for at least 12 months in post-PCI patients treated with coronary stents A GP IIb/IIIa inhibitor may be considered as part of initial antiplatelet therapy in intermediate-/high-risk patients
2014 ESC/EACTS guideline on myocardial revascularization¹⁰	In patients with SCAD undergoing PCI, pretreatment with clopidogrel should be administered >2 h before the procedure. Dual antiplatelet therapy with aspirin and clopidogrel should be continued for at least 1 month after BMS implantation or 6 months after DES implantation (unless patient is at high bleeding risk). Dual antiplatelet therapy may be continued for >6 months in patients at high ischemic risk and low bleeding risk. Shorter dual antiplatelet therapy (<6 months) may be considered after DES implantation in patients at high bleeding risk In NSTE-ACS or STEMI patients undergoing PCI, dual antiplatelet therapy with aspirin and either ticagrelor or prasugrel should be continued for 12 months (in patients without contraindications). Dual antiplatelet therapy with aspirin and clopidogrel can be considered only when prasugrel or ticagrelor is not available or is contraindicated

Abbreviations: ACC, American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; BMS, bare-metal stent; DES, drug-eluting stent; EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of Cardiology; GP IIb/IIIa, glycoprotein IIb/IIIa; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; PCI, percutaneous coronary intervention; SCAD, stable coronary artery disease; STEMI, ST-segment elevation myocardial infarction.

This newsletter aims to summarize the available information pertaining to the use of antiplatelet therapy in high-risk patients (Table 1).

Dual Antiplatelet Therapy vs Aspirin Treatment Alone

In patients at high risk of occlusive vascular events, aspirin has been shown to reduce the rate of major vascular events by approximately 25% vs control.³ Therefore, current guidelines recommend that aspirin should be administered as soon as possible after hospital presentation with an ACS and continued indefinitely in patients in whom the treatment is well tolerated.^6-11 Nevertheless, although aspirin is often thought of as the cornerstone of antithrombotic treatment, it is estimated that 5% to 60% of patients do not benefit from aspirin therapy.¹² A significant number of patients with cardiovascular disease experience a major adverse cardiovascular event while receiving aspirin,¹³ often described as an ‘aspirin treatment failure.’

For the secondary prevention of cardiovascular events in patients with ACS, to ensure adequate inhibition of platelet aggregation, the addition of a P2Y₁₂ receptor antagonist to aspirin therapy is essential. This is of particular importance in patients who have experienced an aspirin treatment failure. In patients with ACS, several studies have shown that the addition of clopidogrel to aspirin is associated with a significant reduction in cardiovascular events and cardiovascular mortality in comparison with aspirin therapy alone, without a significant increase in the risk of major or cerebrovascular bleeding.^14-17 Conversely, some clinical trials have reported that the use of dual antiplatelet therapy (clopidogrel and aspirin) is associated with an increased risk of major bleeding, compared with aspirin monotherapy.^18,19 However, it is thought that the increased bleeding risk is often driven by the aspirin dose used. In patients with STEMI undergoing percutaneous coronary intervention (PCI), high-dose aspirin therapy (>200 mg/day) is independently associated with increased bleeding risk, compared with low-dose aspirin therapy (≤200 mg/day), and does not confer additional cardiovascular benefit.²⁰ Therefore, when administering dual antiplatelet therapy, it is important to use a low aspirin dose.

Despite the clear benefit of dual antiplatelet therapy with clopidogrel in addition to low-dose aspirin in patients with ACS, a substantial number of patients continue to experience thrombotic events.^14-19 This is partly due to the wide variability of response to clopidogrel. Between 5% and 40% of patients have been reported to experience a suboptimal antithrombotic effect with clopidogrel,⁴ which has been shown to lead to stent thrombosis, post-stent ischemic events, and myocardial infarction (MI).²¹

Newer oral P2Y₁₂ receptor antagonists, prasugrel and ticagrelor,^22,23 are now available, and have been shown to be more effective in reducing the rate of cardiovascular events than clopidogrel.^24,25

Available P2Y₁₂ Receptor Antagonists

Like clopidogrel, prasugrel is a pro-drug requiring metabolic activation, but it has a faster onset of action, results in greater platelet inhibition, and is less susceptible to variability in response than clopidogrel.²⁶ The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38) evaluated the safety and efficacy of prasugrel in comparison with clopidogrel in 13,608 patients with moderate- to high-risk ACS undergoing PCI.²⁵ Prasugrel was shown to result in a significantly greater reduction in a composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke during a 15-month follow-up period.²⁵ A significant increase in non-coronary artery bypass graft (non-CABG)-related thrombolysis in myocardial infarction (TIMI) bleeding, including life-threatening bleeding, was reported with prasugrel compared with clopidogrel. However, a significant net clinical benefit was observed overall.²⁵ The greatest net clinical benefit was observed in specific patient populations, particularly those with high cardiovascular risk without an increased risk of bleeding complications, such as those with diabetes or STEMI.^27,28 Conversely, certain patient populations, such as those with a history of stroke or transient ischemic attack (TIA), or those aged ≥75 years or with a body weight of <60 kg, experienced less clinical benefit and greater absolute levels of bleeding than the overall patient population.²⁵ Therefore, prasugrel is contraindicated in patients with prior stroke or TIA, and should be used with caution in patients with risk factors for bleeding, such as elderly patients and those with a low body weight.²³

In contrast to the TRITON–TIMI 38 trial, the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) study, conducted in patients with UA or NSTEMI, showed no significant differences in terms of the primary efficacy end point (death, MI, or stroke) or bleeding risk between prasugrel and clopidogrel.²⁹

Ticagrelor is also a P2Y₁₂ receptor antagonist, but unlike clopidogrel and prasugrel, it inhibits the P2Y₁₂ receptor reversibly and does not require metabolic activation.²² Ticagrelor is now indicated both for the management of patients with ACS and for follow-up treatment in patients with a history of MI. This indication is for the long-term use along with aspirin after the traditional 1-year dual antiplatelet therapy.²² Compared with clopidogrel, ticagrelor has a faster onset of action, results in greater platelet inhibition, and is less susceptible to variability in response.³⁰ The Platelet Inhibition and Patient Outcomes (PLATO) trial assessed the safety and efficacy of ticagrelor in comparison with clopidogrel in 18,624 patients with ACS (including those with STEMI, NSTEMI, and UA) intended for medical and invasive management.²⁴ Ticagrelor was associated with a significantly greater reduction in a composite end point of cardiovascular death, nonfatal MI, and nonfatal stroke and a reduction in all-cause mortality during a 12-month follow-up period.²⁴ There was no significant difference between the treatment groups in terms of major bleeding (study criteria and TIMI), including bleeding requiring red-cell transfusion, or life-threatening or fatal bleeding. However, ticagrelor was associated with significantly more non-CABG-related major bleeding.²⁴The PLATO trial is part of the PARTHENON Clinical Trial Program, which comprises five key large-scale trials and approximately 84,000 patients at high risk of cardiovascular events, and is designed to build scientific understanding of the role of ticagrelor in the treatment of atherothrombotic conditions.

Prasugrel and ticagrelor have increased cardioprotective effects compared with clopidogrel. Although there is an increased bleeding risk associated with these drugs, a significant net clinical benefit is typically observed.^24,27 The 2014 American Heart Association (AHA)/American College of Cardiology (ACC) NSTE-ACS guideline recommends the use of clopidogrel, prasugrel, or ticagrelor in post-PCI patients, and also recommends that ticagrelor should be used in preference to clopidogrel for patients with NSTE-ACS treated with an early invasive or ischemia-guided strategy.¹¹ The key characteristics of the available oral P2Y₁₂ receptor antagonists are summarized in Table 3, and the key data from the three phase 3 clinical trials of dual antiplatelet therapy with aspirin and clopidogrel, prasugrel, or ticagrelor are summarized in Table 4.

Table 3. Available Oral P2Y₁₂ Receptor Antagonists

Agent	Mechanism of P2Y₁₂ inhibition	Indications	Contraindications	Dosage and administration
Clopidogrel⁴⁵	Non-direct (pro-drug), irreversible (thienopyridine)	Indicated for patients with NSTE-ACS, including patients who are to be managed medically and those who are to be managed with coronary revascularization. For patients with STEMI, recent MI, recent stroke, or established PAD	Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage, hypersensitivity to clopidogrel or any component of the product	UA/NSTEMI: 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75–325 mg once daily) STEMI: 75 mg once daily, in combination with aspirin (75–325 mg once daily), with or without a loading dose and with or without thrombolytics Recent MI, recent stroke, or established PAD: 75 mg once daily
Prasugrel²³	Non-direct (pro-drug), irreversible (thienopyridine)	Indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI as follows: patients with UA or NSTEMI; patients with STEMI when managed with either primary or delayed PCI	Active pathological bleeding, prior transient ischemic attack or stroke, hypersensitivity to prasugrel or any component of the product	Initiate treatment with a single 60 mg oral loading dose. Continue at 10 mg once daily with or without food. Consider 5 mg once daily for patients weighing <60 kg. Patients should also take aspirin (75–325 mg) daily
Ticagrelor²²	Direct-acting, reversibly binding (cyclopentyltriazolo-pyrimidine)	Indicated for the reduction of the rate of thrombotic cardiovascular events in patients with ACS (UA, NSTEMI, or STEMI), and for the long-term management of patients with a history of MI	History of intracranial hemorrhage, active pathological bleeding, severe hepatic impairment, hypersensitivity to ticagrelor or any component of the product	Initiate treatment with 180 mg (two 90 mg tablets) oral loading dose. Continue treatment with 90 mg twice daily for the first year after an ACS event. After 1 year administer 60 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), use ticagrelor with a daily maintenance dose of aspirin of 75–100 mg

Abbreviations: ACS, acute coronary syndrome; MI, myocardial infarction; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; NSTEMI, non-ST-segment elevation myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.

Table 4. Key Data From Phase 3 Clinical Trials of Dual Antiplatelet Therapy With P2Y₁₂ Receptor Antagonists and Aspirin

P2Y₁₂ receptor antagonist	Trial	Comparator	Patient population	Primary end point	Key secondary end point(s)	Bleeding end point(s)
Clopidogrel¹⁴	Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE; NCT00222573)	Placebo	Patients with ACS without ST-segment elevation (n=12,562)	Composite of cardiovascular death, nonfatal MI, or stroke: occurred significantly less in the clopidogrel group compared with the placebo group (9.3% vs 11.4% [P < .001]). Composite of cardiovascular death, nonfatal MI, stroke, or refractory ischemia: occurred significantly less in the clopidogrel group, compared with the placebo group (16.5% vs 18.8% [P < .001]).	Severe ischemia: occurred significantly less in the clopidogrel group compared with the placebo group (2.8% vs 3.8% [P = .003]). Heart failure: occurred significantly less in the clopidogrel group, compared with the placebo group (3.7% vs 4.4% [P = .03]). The need for revascularization: no significant difference between the clopidogrel and placebo groups.	Major bleeding: occurred significantly more in the clopidogrel group compared with the placebo group (3.7% vs 2.7% [P = .001]). Life-threatening bleeding: no significant difference between the clopidogrel and placebo groups. Minor bleeding: occurred significantly more in the clopidogrel group, compared with the placebo group (5.1% vs 2.4% [P < .001]).
Prasugrel²⁸	Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38; NCT00097591)	Clopidogrel	Patients with ACS with scheduled PCI (n=13,608)	Composite of cardiovascular death, nonfatal MI, or nonfatal stroke during the follow-up period (15 months): occurred significantly less in the prasugrel group, compared with the clopidogrel group (9.9% vs 12.1% [P < .001]).	Primary composite end point and a composite of cardiovascular death, nonfatal MI, or urgent revascularization at 30 and 90 days: occurred significantly less in the prasugrel group, compared with the clopidogrel group (P < .001). Composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or rehospitalization due to ischemic event for the entire follow-up period (15 months): occurred significantly less in the prasugrel group, compared with the clopidogrel group (P < .001).	Rate of non-CABG-related TIMI major bleeding: significantly higher in the prasugrel group, compared with the clopidogrel group (P = .03). Rate of non-CABG-related TIMI life-threatening bleeding: significantly higher in the prasugrel group, compared with the clopidogrel group (P = .01). Rate of TIMI major or minor bleeding: significantly higher in the prasugrel group, compared with the clopidogrel group (P = .002).
Ticagrelor²⁴	Platelet Inhibition and Patient Outcomes (PLATO; NCT00391872)	Clopidogrel	Patients hospitalized for an ACS (n=18,624).	Composite of cardiovascular death, MI, or stroke: occurred significantly less in the ticagrelor group in comparison with the clopidogrel group (9.8% vs 11.7% [P = .003]).	Primary end point exclusively in invasively treated patients: occurred significantly less in the ticagrelor group in comparison with the clopidogrel group (8.9% vs 10.6% [P = .003]).	Major bleeding (study criteria and TIMI), and bleeding requiring red-cell transfusion, or life-threatening or fatal bleeding: no significant difference between ticagrelor and clopidogrel groups. Non-CABG-related major bleeding (study criteria and TIMI): significantly higher in the ticagrelor group in comparison with the clopidogrel group (P = .03).

Abbreviations: ACS, acute coronary syndrome ; MI, myocardial infarction; non-CABG, non-coronary artery bypass graft; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

Optimal Duration of Dual Antiplatelet Therapy

The optimal duration of dual antiplatelet therapy in patients with ACS undergoing PCI is unclear. The majority of guidelines recommend dual antiplatelet therapy for a maximum of 12 months, unless the increased bleeding risk outweighs the anticipated benefits.^6-10 However, in post-PCI patients treated with coronary stents, a number of guidelines recommend that dual antiplatelet therapy should be continued for at least 12 months.^11,31 The 2013 American College of Cardiology Foundation (ACCF)/AHA STEMI guideline also notes that the continuation of dual antiplatelet therapy beyond 12 months may be considered in patients undergoing drug-eluting stent (DES) placement.⁸ In addition, the 2012 European Society of Cardiology STEMI guideline recommends that dual antiplatelet therapy with aspirin and an oral P2Y₁₂ inhibitor must be continued for up to 12 months after STEMI, with a strict minimum of 1 month for patients receiving a bare-metal stent (BMS), and for a minimum of 6 months in those receiving a DES.⁹ This is in contrast to the 2013 ACCF/AHA STEMI guideline, which recommends that dual antiplatelet therapy should be administered for 12 months, regardless of stent type.⁸

The key data obtained during studies evaluating the optimal duration of dual antiplatelet therapy are summarized in Table 5 and discussed below.

Table 5. Summary of Key Studies Evaluating the Long-term Use of Dual Antiplatelet Therapy in High-risk Patients

Trial	Agent	Patient population	Treatment	Primary end point(s)	Key secondary end point(s)	Safety end point(s)
ARCTIC–Interruption (NCT00827411)⁴⁰	Clopidogrel or prasugrel	n=1259 Patients from the ARCTIC-monitoring trial (scheduled for planned DES implantation and undergoing aspirin-thienopyridine dual antiplatelet therapy for 1 year)	Patients randomized 1:1 to continue aspirin-thienopyridine dual antiplatelet therapy for 6–8 months (continuation group) or continue with aspirin therapy alone (interruption group)	Composite of all-cause mortality, MI, stroke, or TIA, urgent coronary revascularization, and stent thrombosis: no significant difference between treatment groups	Composite of thrombosis and urgent revascularization: no significant difference between treatment groups	Major bleeds: no significant difference between treatment groups Major or minor bleedings combined: significantly increased in the continuation vs the interruption group (1% vs 0.5% [P = .04])
DAPT (NCT00977938)³³	Clopidogrel or prasugrel	n=9961 Candidates for dual antiplatelet therapy after treatment with FDA-approved DES	After 12 months of treatment with a thienopyridine and aspirin, patients were randomized 1:1 to continue thienopyridine therapy or receive placebo for 18 months (30 months in total)	Definite or probable stent thrombosis, major adverse CV and cerebrovascular events: significantly lower in the 30-month treatment group vs the 12-month treatment group (0.4% vs 1.4% [P < .001], and 2.1% vs 4.1% [P < .001], respectively)	Stroke or CV death: no significant difference between the 30-month and 12-month treatment groups All-cause mortality: significantly higher in the 30-month treatment group vs the 12-month treatment group (2.0% vs 1.5% [P = .05])^a	Moderate or severe bleeding: significantly higher in the 30-month treatment group vs the 12-month treatment group (2.5% vs 1.6% [P = .001])
DAPT MI analysis (NCT00977938)³⁴	Clopidogrel or prasugrel	n=11,648 Patients with CAD who received DES or BMS devices with MI (n=3576) or without MI (n=8072)	After 12 months of treatment with a thienopyridine and aspirin, patients were randomized 1:1 to continue thienopyridine therapy or receive placebo for 18 months (30 months in total)	Definite or probable stent thrombosis: significantly lower in the 30-month treatment group vs the 12-month treatment group (0.5% vs 1.9% [P < .001], and 0.4% vs 1.1% [P < .001], for patients with and without MI, respectively) Major adverse CV and cerebrovascular events: significantly lower in the 30-month treatment group vs the 12-month treatment group for patients with MI (3.9% vs 6.8% [P < .001]). No significant difference between the 30-month and 12-month treatment groups for patients without MI	Rate of MI: significantly lower in the 30-month treatment group vs the 12-month treatment group (2.2% vs 5.2% [P < .001], and 2.1% vs 3.5% [P < .001], for patients with and without MI, respectively) All-cause mortality: no significant difference between the 30-month and 12-month treatment groups for patients with MI. Significantly higher in the 30-month treatment group vs 12-month treatment group for patients without MI (2.1% vs 1.5% [P = .04]).	Moderate or severe bleeding: significantly higher in the 30-month treatment group vs the 12-month treatment group (1.9% vs 0.8% [P = .005], and 2.6% vs 1.7% [P = .007], for patients with and without MI, respectively)
CHARISMA (NCT00050817)³⁵	Clopidogrel	n=15,603 Patients with one of the following conditions: atherothrombotic risk factors, documented coronary disease, cerebrovascular disease, or PAD	Patients were randomized to receive clopidogrel plus aspirin or placebo plus aspirin for a median of 28 months	MI, stroke, or CV death: no significant difference between the clopidogrel and placebo treatment groups	First occurrence of MI, stroke, CV death, UA, TIA, or a revascularization procedure: significantly lower in the clopidogrel treatment group vs the placebo treatment group (16.7% vs 17.9% [P = .04])	GUSTO-defined severe bleeding: no significant difference between the clopidogrel and placebo treatment groups Moderate bleeding: significantly higher in the clopidogrel vs placebo treatment group (2.1% vs 1.3% [P < .001])
CHARISMA subgroup analysis (NCT00050817)³⁶	Clopidogrel	n=9478 Patients with documented MI, ischemic stroke, or symptomatic PAD	Patients were randomized to receive clopidogrel plus aspirin or placebo plus aspirin for a median of 28 months	MI, stroke, or CV death: significantly lower in the clopidogrel treatment group vs the placebo treatment group (7.3% vs 8.8% [P = .01])	CV death, MI, stroke, or rehospitalization for UA, TIA, or a revascularization procedure: significantly lower in the clopidogrel treatment group vs the placebo treatment group (17.6% vs 19.8% [P = .004])	GUSTO-defined severe bleeding: no significant difference between the clopidogrel and placebo treatment groups Moderate bleeding: significantly higher in the clopidogrel vs placebo treatment group (2.0% vs 1.3% [P= .004])
ISAR–SAFE (NCT00661206)³⁹	Clopidogrel	n=4000 Patients receiving clopidogrel therapy 6 months after PCI due to symptoms of CAD	At 6 months after PCI, patients on clopidogrel were randomized to 6 months of placebo or an additional 6 months of clopidogrel therapy	Net clinical outcome (composite of death, MI, stent thrombosis [definite or probable], stroke, and TIMI major bleeding) 9 months after randomization: no significant difference between 12- and 6-month dual antiplatelet therapy	Individual components of the primary end point: no significant difference between 12- and 6-month dual antiplatelet therapy	TIMI major or minor bleeding: no significant difference between 12- and 6-month dual antiplatelet therapy BARC bleeding: significantly higher in the 12-month vs 6-month treatment group [P = .002]
ITALIC (NCT01476020)³⁷	Clopidogrel (or prasugrel or ticagrelor)	n=1850 Aspirin-sensitive patients undergoing implantation of everolimus-eluting stents	Patients randomized 1:1 to 6 months vs 24 months of dual antiplatelet therapy (aspirin plus clopidogrel 75 mg/day [or prasugrel 60 mg/day, or ticagrel or 90 mg twice per day])	Composite of death, MI, repeat emergency TVR, stroke, or TIMI major bleeding within 12 months of stenting: no significant difference between treatment groups Noninferiority was established for 6- vs 24-month dual antiplatelet therapy (P_{for noninferiority}= .0002)	All individual end points used in the composite major adverse coronary event score: no significant difference between treatment groups	Bleeding complications (according to TIMI criteria): no significant difference between treatment groups
PEGASUS–TIMI 54 (part of the Parthenon Clinical Trial Program) (NCT01225562)³²	Ticagrelor	n=21,162 Patients who had an MI 1–3 years before enrollment	Randomized 1:1:1 to receive ticagrelor 90 mg twice daily, 60 mg twice daily, or placebo Median duration of follow-up: 33 months	Composite of CV death, MI, or stroke at 3 years vs placebo: significantly reduced with ticagrelor 90 mg (7.85% [P = .008]) and 60 mg (7.77% [P = .004]) vs placebo	CV death: Non-significant reduction with ticagrelor All-cause mortality: No significant difference with either ticagrelor dose vs placebo	TIMI major bleeding: significantly increased with ticagrelor 90 mg and 60 mg vs placebo (2.6% [P < .001] and 2.3% [P < .001], respectively) Intracranial hemorrhage or fatal bleeding: No significant difference between ticagrelor 90 mg (0.63%) or 60 mg (0.71%) and placebo (0.60%).
SECURITY (NCT00944333)³⁸	Clopidogrel	n=1399 Patients with a stable or unstable angina diagnosis or documented silent ischemia undergoing revascularization with at least 1 second-generation DES	Patients randomized 1:1 to receive clopidogrel 75 mg for 6 months or 12 months of dual antiplatelet therapy (aspirin was prescribed indefinitely)	Composite of CV death, MI, stroke, definite or probable stent thrombosis, or BARC type 3 or 5 bleeding: no significant difference between treatment groups Noninferiority was established for 6- vs 24-month dual antiplatelet therapy (P_{for noninferiority}< .05)	Composite of cardiac death, MI, stroke, definite or probable BARC type 2, 3, or 5 bleeding at 12 and 24 months: no significant difference between treatment groups All-cause mortality: no significant difference between treatment groups	Bleeding events (according to TIMI and GUSTO criteria) at any time point: no significant difference between treatment groups
TRILOGY ACS (NCT00699998)²⁹	Prasugrel	n=9326 Patients with ACS selected for a final treatment strategy of medical management without revascularization within 10 days after the index event, and with at least one of the four risk criteria: aged <60 years, diabetes mellitus, previous MI, or previous revascularization with either PCI or CABG	Patients randomized to receive prasugrel or clopidogrel (with concomitant aspirin) for 6–30 months	Composite of CV death, nonfatal MI, or nonfatal stroke among patients <75 years: no significant difference between treatment groups at a mean follow-up of 17 months	CV death, MI, and stroke: no significant difference between treatment groups at a mean follow-up of 30 months	Severe or life-threatening non-CABG-related bleeding or non-CABG-related TIMI major bleeding: no significant difference between treatment groups at a mean follow-up of 30 months

^aThese differences were not significant when patients with a history of cancer were excluded.

Abbreviations: ACS, acute coronary syndrome; ARCTIC, Assessment by a double Randomisation of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and of Treatment Interruption versus Continuation 1 year after stenting; BARC, Bleeding Academic Research Consortium; BMS, bare-metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CV, cardiovascular; DAPT, Dual AntiPlatelet Therapy; DES, drug-eluting stent; FDA, US Food and Drug Administration; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; ISAR–SAFE, Intracoronary Stenting and Antithrombotic Regimen: Safety and EFicacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC, Is There A LIfe for Drug-Eluting Stent After Discontinuation of Clopidogrel; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; PEGASUS–TIMI, Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction; SECURITY, Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy; TIA, transient ischemic attack; TIMI, Thrombolysis in Myocardial Infarction; TRILOGY, Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes; TVR, target vessel revascularization; UA, unstable angina.

In the recent Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS–TIMI 54) trial (n=21,162), long-term dual antiplatelet therapy with ticagrelor (60 mg or 90 mg twice daily) and aspirin significantly reduced the composite end point of cardiovascular death, MI, and stroke during a 3-year follow-up period in comparison with aspirin therapy alone in patients with prior MI³²(Figure 2). Dual antiplatelet therapy was associated with a significant increase in the rates of TIMI major bleeding, compared with aspirin monotherapy, but this did not include significant increases in intracranial hemorrhage or fatal bleeding.³² Based on the results of this study, the ticagrelor US prescribing information was updated in September 2015 to include ticagrelor 60 mg, in combination with low-dose aspirin, as preventive therapy for the long-term management of patients with a history of MI to continue long term after the traditional 1 year of treatment.²²

Figure 2. Results From the PEGASUS Study: Kaplan-Meier Rates of Cardiovascular Death, Myocardial Infarction, and Stroke Through 3 Years, According To Study Group

Study drugs were administered twice daily. The inset shows the same data on an enlarged y-axis

From Bonaca et al 2015.³²

From N Engl J Med, Bonaca MP, Bhatt DL, Cohen, et al, Long term use of ticagrelor in patients with prior myocardial infarction, Vol. 371, 2155-2166.
Copyright © (2015) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

In the Dual AntiPlatelet Therapy (DAPT) study, following DES or BMS placement, patients were administered dual antiplatelet therapy (aspirin with either prasugrel or clopidogrel) for 12 months. At 12 months 9961 patients were randomized to continue dual antiplatelet therapy (30-month treatment group) or placebo (12-month treatment group) for an additional 18 months.³³ Whereas the rates of stent thrombosis and major cardiovascular and cerebrovascular events were significantly lower with 30 months compared with 12 months of dual antiplatelet therapy, the rates of moderate or severe bleeding and all-cause mortality were significantly higher in patients who continued treatment up to 30 months.³³ That being said, a blinded review of cancer-related deaths identified a between-group imbalance, and once patients diagnosed with cancer prior to randomization were excluded from the analysis, differences in all-cause mortality were no longer significant.³³ In addition, a recent subgroup analysis from the DAPT study assessed the benefits and risks of 30 vs 12 months of dual antiplatelet therapy in patients undergoing PCI with or without MI (n=3576 and n=8072, respectively).³⁴ The results showed that 30 months of dual antiplatelet therapy significantly reduced the rate of stent thrombosis and significantly increased the rate of bleeding in both patient subgroups, whereas the incidence of major cardiovascular and cerebrovascular events was significantly reduced in the MI patient subgroup only.³⁴

In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial (n=15,603), dual antiplatelet therapy with aspirin and clopidogrel administered for a median of 27.6 months was shown to have no significant benefit in a population of patients with stable cardiovascular disease or multiple cardiovascular risk factors.³⁵ However, a post-hoc analysis of the subgroup of patients with documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease (n=9478) found that dual antiplatelet therapy was associated with a significant reduction in the composite end point of cardiovascular death, MI, or stroke compared with aspirin therapy alone. This suggests that there is a gradient of benefit for the use of long-term dual antiplatelet therapy depending on the patient’s level of thrombotic risk.³⁶

Several other large-scale clinical trials assessing the long-term use of dual antiplatelet therapy with either clopidogrel or prasugrel and aspirin have reported no significant differences in clinical outcomes between long-term (>12 months) and short-term (<6 months) dual antiplatelet therapy, including rates of cardiovascular events, all-cause mortality, and bleeding complications.^29,37,38 Furthermore, despite showing no significant differences between short- and long-term dual antiplatelet therapy in terms of cardiovascular risk reduction, other studies have reported increases in Bleeding Academic Research Consortium (BARC) bleeding³⁹ or TIMI major and minor bleeding combined.⁴⁰ A number of recent meta-analyses evaluating the optimal duration of dual antiplatelet therapy have found that long-term dual antiplatelet therapy (>12 months) is associated with a significant reduction in the risk of MI and stent thrombosis and a significant increase in the risk of major bleeding.^41,42 Although some meta-analyses have reported a significant increase in the risk of all-cause mortality with long-term dual antiplatelet therapy in comparison with short-term,⁴¹ some have reported no significant difference.⁴²

It is worth noting that the PEGASUS–TIMI 54 trial is the only long-term study of dual antiplatelet therapy conducted solely in patients with prior MI.³² Other studies were conducted in patients with stable coronary artery disease and ACS and, with the exception of the DAPT and CHARISMA studies,^33,36 were limited by sample size and included more patients with stable coronary artery disease than patients with MI.^29,34,37-40 These differences in patient population may account for some of the heterogeneity in results observed among studies.

Overall, the results suggest that the duration of dual antiplatelet therapy should be tailored to the individual patient.^43,44 The cardiovascular risks associated with the discontinuation of dual antiplatelet therapy, and the increased bleeding risk associated with the continuation of dual antiplatelet therapy for >12 months, should both be considered. It is thought that patients at high risk of a recurrent cardiovascular event and at low risk of bleeding complications may benefit most from the prolonged (>12 months) use of dual antiplatelet therapy. However, additional clinical trials will be required to further establish the optimal duration of dual antiplatelet therapy. A list of key ongoing clinical trials evaluating the long-term use of clopidogrel, prasugrel, and ticagrelor is shown in Table 6.

Table 6. Ongoing Large-Scale (n≥1000) Outcomes Studies (Phase 3 or 4) Evaluating the Long-Term (>12 Months) Use of Clopidogrel, Prasugrel, or Ticagrelor

Study	Agent	Start date/ estimated completion date	Patient population	Estimated enrolment	Treatment	Primary outcome measures	Secondary outcome measures
TWILIGHT (NCT02270242)⁴⁸	Ticagrelor	December 2014/ October 2017	High-risk patients who have had a PCI with ≥1 DES	9000	Patients randomized to either ticagrelor plus aspirin or ticagrelor plus placebo. Follow-up performed at 3, 9, and 15 months	Time to first occurrence of BARC bleeding type 2, 3, or 5	Time to first occurrence of confirmed CV death, nonfatal MI, IS, or ischemia-driven revascularization
THEMIS (part of the PARTHENON Clinical Trial Program)(NCT01991795)⁴⁹	Ticagrelor	February 2014/ June 2017	Patients with type 2 diabetes mellitus and either documented coronary artery occlusive disease or previous revascularization of a coronary artery	17,000	Patients randomized to ticagrelor or placebo (35-month time frame)	Composite of CV death, MI, or stroke	CV death, MI, IS, or all-cause mortality
EUCLID (part of the PARTHENON Clinical Trial Program) (NCT01732822)⁵⁰	Ticagrelor or clopidogrel	December 2012/ July 2016	Patients with symptomatic PAD	13,500	Randomized to ticagrelor or placebo (40-month time frame)	Composite of CV death, MI, and IS	CV death, MI, IS, and ALI, all-cause mortality, lower- extremity revascularization, or any revascularization
Twelve vs 24 Months of Dual Antiplatelet Therapy in Patients With Coronary Revascularization for ISR (NCT02402491)⁵¹	Ticagrelor, prasugrel or clopidogrel	January 2013/ June 2015	Patients undergoing PCI for ISR	1000	Patients randomized to receive either 12 months or 24 months of dual antiplatelet therapy (P2Y₁₂ inhibitor and aspirin)	MACCE	Incidence of GUSTO moderate or severe bleeding
STAMP–DES (NCT02494284)⁵²	Clopidogrel	June 2015/ December 2018	Patients undergoing a zotarolimus-eluting stent implantation	1398	Patients randomized to receive 6 months of dual antiplatelet therapy (aspirin and clopidogrel) followed by clopidogrel monotherapy vs 24 months of dual antiplatelet therapy followed by aspirin monotherapy	Number of participants with BARC bleeding type 2, 3, or 5	CV death, MI, stroke, stent thrombosis, repeat revascularization, BARC bleeding type 3 or 5; composite of CV death or MI; composite of CV death, MI, stroke, or stent thrombosis; gastrointestinal effects; composite of BARC bleeding type 2, 3, 5 or gastrointestinal side effects
Global leaders: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation (NCT01813435)⁵³	Ticagrelor or clopidogrel	May 2013/ October 2016	Patients undergoing PCI	16,000	Patients randomized to receive dual antiplatelet therapy (ticagrelor with aspirin) for 1 month, and then ticagrelor alone for an additional 23 months or standard treatment (dual antiplatelet therapy with aspirin and either ticagrelor or clopidogrel for 12 months, and then aspirin alone indefinitely)	Composite of all-cause mortality or non-fatal new Q-wave MI up to 2 years post-randomization	Composite of investigator-reported BARC3 or BARC5 bleeding up to 2 years post-randomization

Abbreviations: ALI, acute lung injury; BARC, Bleeding Academic Research Consortium; CV, cardiovascular; DES, drug-eluting stent; EUCLID, Examining Use of Ticagrelor In PAD; GUSTO, Global Utilization of Streptokinase and Tpa for Occluded Arteries; IS, ischemic stroke; ISR, in-stent restenosis; MACCE, major adverse clinical cardiovascular events; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; STAMP–DES, Short-Term Dual Antiplatelet and Maintenance CloPidogrel Therapy after Drug-Eluting Stent Implantation; THEMIS, Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study; TWILIGHT, Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention.

Conclusions

In most high-risk patients with ACS, there is a clear clinical benefit of dual antiplatelet therapy (a P2Y₁₂ receptor antagonist plus low-dose aspirin), in comparison with aspirin therapy alone. Studies have shown that in high-risk patients, prasugrel and ticagrelor are associated with significant reductions in cardiovascular event rates compared with clopidogrel, but with increased major bleeding in some studies. The optimal duration of dual antiplatelet therapy in patients with ACS remains unclear, with guidelines differing in their treatment recommendations. Both the PEGASUS–TIMI 54 and DAPT studies have shown that prolonged dual antiplatelet therapy (>12 months) significantly reduces the risk of cardiovascular events, but also increases the risk of major bleeding. Therefore, it is recommended that the duration of dual antiplatelet therapy should be tailored to the individual patient. Patients at high cardiovascular risk and at low bleeding risk may benefit most from the prolonged (>12 months) use of dual antiplatelet therapy. As a result of the PEGASUS–TIMI 54 study, the ticagrelor US prescribing information has been updated to include the long-term management of patients with a history of MI to continue after the previous 1-year period²² and it is likely that, in time, this will influence future guidelines on dual antiplatelet therapy and the total long-term treatment algorithm. The key implications for clinical practice are summarized in Table 7.

Table 7. Key Implications for Clinical Practice

In high-risk patients with ACS, dual antiplatelet therapy with a P2Y₁₂ receptor antagonist and low-dose aspirin should be administered as soon as possible after the acute cardiovascular event.
In high-risk patients, prasugrel and ticagrelor are associated with significant reductions in cardiovascular event rates compared with clopidogrel, but with increased bleeding in some studies.
The optimal duration of dual antiplatelet therapy is unclear, and treatment should be tailored to the individual patient.
In patients with ACS undergoing PCI, current guidelines recommend dual antiplatelet therapy for up to or at least 12 months, unless bleeding risk outweighs the anticipated benefits.
Patients at high cardiovascular risk and at low bleeding risk may benefit from prolonged (>12 months) use of dual antiplatelet therapy.

Abbreviations: ACS, acute coronary syndromes, PCI, percutaneous coronary intervention.

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