New England Journal of Medicine MAY 07, 2015

Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction

Bonaca MP, Bhatt DL, Cohen M, et al.

Bottom Line

In stable patients with a history of myocardial infarction, long-term dual antiplatelet therapy with ticagrelor and aspirin reduced the risk of major adverse cardiovascular events compared to aspirin alone, albeit with an increased risk of major bleeding.

Key Findings

1. Ticagrelor (both 60 mg and 90 mg twice daily) added to low-dose aspirin significantly reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to placebo at 3 years (7.8% vs. 9.0%; hazard ratio [HR] 0.84-0.85; p < 0.01).

2. The benefit in ischemic event reduction was achieved at the cost of a higher incidence of TIMI major bleeding with ticagrelor (2.3%–2.6% vs. 1.06% for placebo; HR 2.32–2.71; p < 0.001).

3. There was no significant increase in intracranial hemorrhage or fatal bleeding, indicating that the bleeding risk, while increased, did not manifest as a catastrophic safety signal.

4. The 60 mg dose showed a comparable efficacy profile to the 90 mg dose with potentially better long-term tolerability, leading to its subsequent adoption in clinical practice for this indication.

Study Design

Design

RCT

Double-Blind

Sample

21,162

Patients

Duration

33 mo

Median

Setting

Multinational

Population Patients aged 50 or older with a spontaneous myocardial infarction 1 to 3 years prior to enrollment and at least one additional high-risk feature (e.g., age ≥65, diabetes, multi-vessel CAD, or chronic kidney disease).

Intervention Ticagrelor 60 mg or 90 mg twice daily plus low-dose aspirin.

Comparator Matching placebo plus low-dose aspirin.

Outcome Composite of cardiovascular death, myocardial infarction, or stroke.

Study Limitations

• The trial demonstrated a trade-off between reduced ischemic events and increased major bleeding, necessitating careful patient selection to optimize the net clinical benefit.

• The trial included patients who were generally stable for 1 to 3 years post-MI, which may limit the generalizability of these findings to patients with more recent or much older MI events.

• The study required patients to be on antiplatelet therapy at the time of enrollment (or shortly after discontinuation), which may introduce selection bias regarding patients who were already tolerating such therapy well.

Clinical Significance

The PEGASUS-TIMI 54 trial provided the evidentiary basis for the long-term use of dual antiplatelet therapy (DAPT) with low-dose ticagrelor and aspirin for secondary prevention in high-risk patients with a history of MI beyond the initial 12-month post-event window, shifting the paradigm of chronic post-MI management.

Historical Context

Prior to PEGASUS-TIMI 54, standard clinical practice for post-MI patients was to limit DAPT to approximately 12 months, based on the assumption that the risks of bleeding outweighed the ischemic benefits beyond that timeframe; this trial challenged that conventional wisdom and established a role for extended duration therapy in selected high-risk patients.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale for targeting the P2Y12 receptor in addition to the COX-1 pathway (via aspirin) for long-term secondary prevention in post-myocardial infarction patients?

Key Response

Aspirin inhibits thromboxane A2 production, but platelet activation is multifactorial. The P2Y12 receptor is a key mediator of ADP-induced platelet aggregation. Dual antiplatelet therapy (DAPT) provides synergistic inhibition of platelet thrombus formation, which is critical because patients with a prior MI remain at high risk for recurrent atherothrombotic events even years after the index event.

Resident

In a patient who has completed 12 months of DAPT after a STEMI without bleeding complications, what clinical factors from the PEGASUS-TIMI 54 trial would lead you to recommend extending ticagrelor at the 60 mg BID dose rather than stopping the P2Y12 inhibitor?

Key Response

The trial demonstrated that extending ticagrelor reduced MACE (CV death, MI, or stroke). Residents should identify high-ischemic-risk features such as age over 65, diabetes mellitus, a second prior MI, multivessel coronary artery disease, or chronic kidney disease. If the patient has tolerated the first year of DAPT without bleeding, the 'net clinical benefit' favors extension in these high-risk subgroups.

Fellow

The PEGASUS-TIMI 54 trial compared 90 mg and 60 mg doses of ticagrelor. While both were effective, the 60 mg dose is now the standard for long-term use. Analyze the data regarding side-effect profiles—specifically dyspnea and bleeding—that justify this dosing preference.

Key Response

Both doses (90mg and 60mg) significantly reduced MACE with similar hazard ratios (~0.85). However, the 60 mg dose showed a numerically lower rate of TIMI major bleeding and a lower rate of permanent discontinuation due to adverse events like dyspnea (16% vs 19%) compared to the 90 mg dose. This suggests the 60 mg dose sits at a more favorable point on the dose-response curve for long-term tolerability.

Attending

How does the 'timing of transition' from the initial post-MI DAPT phase to the PEGASUS-style extended therapy impact real-world outcomes, particularly concerning the gap between the 12-month mark and the initiation of extended therapy?

Key Response

Sub-analyses of PEGASUS-TIMI 54 indicated that the benefit of ticagrelor was greatest in those who continued therapy without a significant interruption (less than 30 days) after the initial 12-month post-MI period. The 'attending-level' insight is that the benefit of restarting a P2Y12 inhibitor in a patient who has been off it for years is much less clear than simply not stopping it in a high-risk patient.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of the TIMI major bleeding classification in PEGASUS-TIMI 54 versus other bleeding scales like BARC or GUSTO. How might the choice of bleeding endpoint influence the reported Safety-to-Efficacy ratio in a long-term maintenance trial?

Key Response

TIMI major bleeding is a stringent, clinically significant endpoint (intracranial hemorrhage or drop in Hgb >5g/dL). While it captures the most severe events, it may under-represent the 'nuisance bleeding' that leads to high discontinuation rates (as seen in the 30% dropout in this study). A PhD researcher would note that using a more sensitive scale like BARC (Bleeding Academic Research Consortium) might provide a better understanding of the relationship between non-adherence and treatment efficacy.

Journal Editor

The trial reported a high rate of study drug discontinuation (~30%). As an editor, how would you evaluate the threat this poses to the validity of the reported Hazard Ratios for the primary efficacy endpoint in an Intention-To-Treat (ITT) analysis?

Key Response

In ITT analysis, high discontinuation rates typically bias the results toward the null. Since ticagrelor still showed a statistically significant 15% reduction in MACE despite 30% of patients stopping the drug, the 'true' biologic effect in compliant patients (per-protocol) is likely even stronger. However, an editor would flag that the high dropout rate limits the generalizability of the therapy's real-world effectiveness due to poor long-term tolerability.

Guideline Committee

Based on PEGASUS-TIMI 54, current ESC and ACC/AHA guidelines have updated the recommendation for extended DAPT. What are the specific criteria for a 'Class II' recommendation for ticagrelor 60 mg BID beyond 12 months in current clinical practice?

Key Response

Guidelines (e.g., 2016 ACC/AHA Focused Update on Duration of DAPT and 2023 ESC ACS Guidelines) now suggest that in patients with high ischemic risk and no high bleeding risk, extending DAPT beyond 12 months is 'reasonable' (Class IIa or IIb). High ischemic risk is often defined by the presence of multivessel disease plus at least one other risk factor (DM, renal failure, etc.). The recommendation specifically highlights the 60 mg dose of ticagrelor based on the PEGASUS-TIMI 54 evidence of maintained efficacy with improved safety over the 90 mg dose.

Clinical Landscape

Noteworthy Related Trials

1996

CAPRIE Trial

n = 19,185 · Lancet

Tested

Clopidogrel 75mg daily

Population

Patients with recent myocardial infarction, recent stroke, or established peripheral arterial disease

Comparator

Aspirin 325mg daily

Endpoint

Composite of ischemic stroke, myocardial infarction, or vascular death

Key result: Clopidogrel was slightly more effective than aspirin in reducing the risk of ischemic events in patients with symptomatic atherosclerotic disease.

2009

PLATO Trial

n = 18,624 · NEJM

Tested

Ticagrelor

Population

Patients hospitalized with acute coronary syndromes

Comparator

Clopidogrel

Endpoint

Composite of death from vascular causes, myocardial infarction, or stroke

Key result: Ticagrelor significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke compared with clopidogrel without an increase in major bleeding.

2014

DAPT Study

n = 9,961 · NEJM

Tested

Continued dual antiplatelet therapy (thienopyridine + aspirin) for 30 months

Population

Patients who had successfully completed 12 months of dual antiplatelet therapy after coronary stent placement

Comparator

Placebo + aspirin

Endpoint

Composite of death, MI, or stroke at 30 months

Key result: Extended dual antiplatelet therapy beyond 1 year significantly reduced the risk of stent thrombosis and major adverse cardiovascular and cerebrovascular events but increased bleeding risk.

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