New England Journal of Medicine May 07, 2015

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

Marc P Bonaca, Deepak L Bhatt, Marc Cohen, Philippe Gabriel Steg, Robert F Storey et al.

Bottom Line

In stable patients with a history of myocardial infarction 1 to 3 years prior, long-term therapy with ticagrelor added to aspirin significantly reduced the composite risk of cardiovascular death, myocardial infarction, or stroke, but at the cost of increased major bleeding.

Key Findings

1. The primary efficacy endpoint (composite of cardiovascular death, MI, or stroke) at 3 years occurred in 7.85% of patients taking 90 mg of ticagrelor twice daily, 7.77% taking 60 mg, and 9.04% on placebo.

2. Ticagrelor 90 mg twice daily significantly reduced the primary endpoint compared to placebo (HR 0.85; 95% CI, 0.75 to 0.96; P=0.008), as did ticagrelor 60 mg twice daily (HR 0.84; 95% CI, 0.74 to 0.95; P=0.004).

3. Rates of TIMI major bleeding were significantly higher with both the 90 mg dose (2.60%) and the 60 mg dose (2.30%) compared with placebo (1.06%) (P<0.001 for each dose vs. placebo).

4. There was no significant increase in the rates of intracranial hemorrhage or fatal bleeding, which occurred in 0.63% of the 90 mg group, 0.71% of the 60 mg group, and 0.60% of the placebo group.

5. Premature treatment discontinuation was frequent, occurring in 32% of patients in the 90 mg group, 29% in the 60 mg group, and 21% in the placebo group, driven primarily by adverse events such as dyspnea and non-major bleeding.

Study Design

Design

RCT

Double-Blind

Sample

21,162

Patients

Duration

33 mo

Median

Setting

Global multicenter

Population Stable patients aged 50 years or older who had a spontaneous myocardial infarction 1 to 3 years prior to enrollment and had at least one additional atherothrombotic risk factor (e.g., age ≥65, diabetes mellitus, a second prior MI, multivessel coronary artery disease, or chronic renal dysfunction).

Intervention Ticagrelor 90 mg twice daily or ticagrelor 60 mg twice daily (both on a background of low-dose aspirin 75-150 mg daily).

Comparator Placebo twice daily (on a background of low-dose aspirin 75-150 mg daily).

Outcome A composite of cardiovascular death, myocardial infarction, or stroke.

Study Limitations

• High rates of premature study drug discontinuation (up to 32% in the treatment arms), primarily due to dyspnea and non-major bleeding, which may impact real-world medication adherence.

• The absolute risk reduction for the primary ischemic outcome was relatively modest (approximately 1.2% to 1.3%), requiring a careful weighing against the absolute increase in major bleeding.

• The study excluded patients with a high risk of bleeding, prior stroke, or a need for chronic anticoagulation, thereby limiting the generalizability of the findings to these higher-risk subgroups.

• The trial did not demonstrate a statistically significant reduction in all-cause mortality or cardiovascular death individually.

Clinical Significance

PEGASUS-TIMI 54 fundamentally shifted the clinical paradigm for secondary prevention in post-myocardial infarction care. It established the efficacy of extending dual antiplatelet therapy (DAPT) beyond the traditional 1-year post-MI window for high-risk patients. Crucially, the trial highlighted that the lower 60 mg twice-daily dose of ticagrelor offered robust ischemic protection similar to the 90 mg dose but with a slightly more favorable tolerability profile, leading to its FDA approval for long-term extended use in appropriate patients.

Historical Context

Prior to this trial, dual antiplatelet therapy combining aspirin and a P2Y12 inhibitor was definitively established as the standard of care for the first 12 months following an acute coronary syndrome, a practice largely shaped by landmark trials like CURE, TRITON-TIMI 38, and PLATO [1]. However, the benefit of maintaining DAPT beyond 1 year remained uncertain. While the contemporary DAPT trial demonstrated benefits of extended therapy specifically in patients who had received coronary stents, PEGASUS-TIMI 54 proved that prolonged P2Y12 inhibition reduced long-term atherothrombotic risk in a broader demographic of stable high-risk patients who had survived an MI, shaping modern guidelines on extended DAPT.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the mechanism of action of ticagrelor, and how does it differ pharmacologically from clopidogrel in terms of metabolism and receptor binding?

Key Response

Ticagrelor is a direct-acting, reversible P2Y12 receptor antagonist, whereas clopidogrel is an irreversible thienopyridine prodrug requiring hepatic CYP2C19 activation. This explains ticagrelor's faster onset and offset, as well as its lack of variability based on CYP2C19 genetic polymorphisms.

Resident

Based on the PEGASUS-TIMI 54 trial, how should you risk-stratify a patient who is 1 year post-MI to decide if they should continue DAPT with ticagrelor rather than stopping the P2Y12 inhibitor?

Key Response

The trial enrolled patients with a history of MI 1 to 3 years prior who had at least one additional high-risk feature such as age over 65, diabetes mellitus, a second prior MI, multivessel CAD, or chronic renal dysfunction. Residents must weigh these ischemic risk factors against the patient's bleeding risk to make an individualized decision about extending DAPT.

Fellow

The trial tested both 90 mg BID and 60 mg BID dosing of ticagrelor. How did the outcomes between these two doses differ, and how does this influence the choice of maintenance dose for prolonged DAPT in cardiology practice?

Key Response

Both doses significantly reduced the primary ischemic endpoint compared to placebo. However, the 60 mg BID dose had lower rates of dyspnea and treatment discontinuation compared to the 90 mg BID dose, resulting in a more favorable overall risk-benefit ratio. Consequently, 60 mg BID is the preferred and approved dose for extended DAPT beyond 1 year post-MI.

Attending

How do you balance the NNT for ischemic benefit versus the NNH for major bleeding seen in PEGASUS-TIMI 54 when engaging in shared decision-making with a patient considering prolonged DAPT?

Key Response

Over 3 years, the absolute risk reduction for the primary efficacy endpoint was roughly 1.2 percent (NNT around 84), while the absolute risk increase for TIMI major bleeding was also roughly 1.2 percent (NNH around 84) with the 60mg dose. Attendings must navigate this equivalence by highlighting that fatal bleeding and intracranial hemorrhage did not significantly increase, making therapy highly dependent on patient values regarding bleeding versus re-infarction.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial required patients to have had an MI 1 to 3 years prior to enrollment. What is the methodological rationale for this specific window, and how does the concept of time since P2Y12 inhibitor withdrawal introduce a potential selection bias in the study design?

Key Response

The 1 to 3 year window captured patients in the chronic phase, but subgroup analyses later showed the benefit was overwhelmingly concentrated in patients who started ticagrelor within 30 days of stopping their previous P2Y12 inhibitor. Methodologically, patients who tolerated DAPT for a year without bleeding and immediately enrolled represent a highly selected cohort, limiting generalizability to patients who have been off DAPT for longer periods.

Journal Editor

As a reviewer, how would you critically evaluate the high discontinuation rates of the study drug (over 30 percent in the 90 mg arm and over 28 percent in the 60 mg arm), and what impact does this have on the validity of the intention-to-treat analysis?

Key Response

High discontinuation rates, primarily driven by adverse events like dyspnea and bleeding, threaten the trial validity by diluting the observed treatment effect in an intention-to-treat analysis. An editor would flag this because the true biological efficacy might be underestimated, while the high safety and tolerability concerns clearly hinder real-world adherence, making per-protocol analyses essential for context.

Guideline Committee

How do the findings of PEGASUS-TIMI 54 integrate into the ACC/AHA guidelines for the duration of DAPT in patients with stable ischemic heart disease, specifically regarding the strength of recommendation for prolonged therapy?

Key Response

The evidence from PEGASUS-TIMI 54 led guidelines to give a Class IIb recommendation for extending DAPT beyond 1 year in patients with prior MI who have tolerated DAPT without a bleeding complication and have high ischemic risk. The committee must emphasize that routine extension is not a Class I recommendation due to the obligate increase in major bleeding, necessitating the use of tools like the DAPT score to guide this decision.

Clinical Landscape

Noteworthy Related Trials

2009

PLATO Trial

n = 18,624 · NEJM

Tested

Ticagrelor 90mg twice daily plus aspirin

Population

Patients with acute coronary syndromes

Comparator

Clopidogrel 75mg daily plus aspirin

Endpoint

Composite of CV death, MI, or stroke

Key result: Ticagrelor significantly reduced the rate of the primary endpoint compared to clopidogrel without a significant increase in overall major bleeding.

2014

DAPT Trial

n = 9,961 · NEJM

Tested

30 months of dual antiplatelet therapy (thienopyridine plus aspirin)

Population

Patients who had undergone coronary stenting

Comparator

12 months of dual antiplatelet therapy (placebo plus aspirin)

Endpoint

Stent thrombosis and major adverse cardiovascular and cerebrovascular events

Key result: Extended DAPT reduced the risks of stent thrombosis and major adverse cardiovascular events but increased the risk of moderate or severe bleeding.

2017

COMPASS Trial

n = 27,395 · NEJM

Tested

Rivaroxaban 2.5mg twice daily plus aspirin

Population

Patients with stable atherosclerotic vascular disease

Comparator

Aspirin alone

Endpoint

Composite of CV death, stroke, or MI

Key result: The combination of low-dose rivaroxaban and aspirin yielded better cardiovascular outcomes than aspirin alone, albeit with more major bleeding.

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