Article Identification

  • Article Title: Long-term use of ticagrelor in patients with prior myocardial infarction
  • Citation: Bonaca MP, et al. N Engl J Med. 2015;372(19):1791-1800.
  • DOI/PMID: DOI: 10.1056/NEJMoa1500963, PMID: 25985371

Quick Reference Summary

  • Extended dual antiplatelet therapy with ticagrelor significantly reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (7.85% and 7.77% with ticagrelor 90 mg and 60 mg twice daily, respectively) compared to placebo (9.04%) with statistical significance (P=0.008 and P=0.004).
  • However, ticagrelor increased the risk of TIMI major bleeding (2.60% and 2.30% vs. 1.06%, P<0.001 for both doses).

Core Clinical Question

Does long-term ticagrelor therapy in patients with a history of myocardial infarction more than one year prior reduce the incidence of major cardiovascular events compared to placebo, and what are the associated risks?

Background

  • Disease Overview:
    • Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide.
    • Post-MI patients are at elevated risk for recurrent ischemic events, necessitating effective secondary prevention strategies.
  • Prior Data:
    • Aspirin reduces ischemic events in both acute and secondary prevention settings.
    • P2Y12 receptor antagonists (e.g., clopidogrel) added to aspirin have shown efficacy in reducing ischemic events within the first year post-acute coronary syndrome (ACS).
  • Current Standard of Care:
    • Guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor for up to one year following MI.
    • Long-term DAPT beyond one year has not been established as standard practice.
  • Knowledge Gaps Addressed:
    • Efficacy and safety of extending DAPT with ticagrelor beyond one year post-MI.
    • Optimal duration and dosage of ticagrelor for long-term secondary prevention.
  • Study Rationale:
    • To determine whether prolonged antiplatelet therapy with ticagrelor provides additional cardiovascular benefits in stable post-MI patients without significantly increasing bleeding risks.

Methods Summary

  • Study Design: Randomized, double-blind, placebo-controlled clinical trial.
  • Setting/Time Period: 1,161 sites across 31 countries; patients randomized from October 2010 to May 2013.
  • Population Characteristics: 21,162 patients ≥50 years old with a history of spontaneous MI 1-3 years prior and at least one additional high-risk feature (e.g., age ≥65, diabetes, multivessel disease).
  • Inclusion/Exclusion Criteria: Included patients on low-dose aspirin; excluded those with planned P2Y12 antagonist use, bleeding disorders, recent bleeding, intracranial hemorrhage, etc.
  • Interventions: Ticagrelor 90 mg twice daily or 60 mg twice daily added to low-dose aspirin.
  • Control/Comparison Group: Placebo added to low-dose aspirin.
  • Primary/Secondary Outcomes:
    • Primary Efficacy: Composite of cardiovascular death, MI, or stroke.
    • Primary Safety: TIMI major bleeding.
    • Secondary Outcomes: Cardiovascular death, all-cause death, and other exploratory endpoints.
  • Statistical Analysis: Intention-to-treat; Cox proportional-hazards model; Kaplan–Meier estimates; hazard ratios with 95% confidence intervals; significance level adjusted for interim analysis.
  • Sample Size Calculation: Powered to detect ~20% relative risk reduction with ticagrelor doses compared to placebo.
  • Ethics and Funding: Funded by AstraZeneca; clinical trial registered as NCT01225562; no reported conflicts of interest beyond sponsor funding.

Detailed Results

  • Participant Flow and Demographics:
    • 21,162 patients randomized; 99.0% received at least one dose of study drug.
    • Baseline characteristics were well-balanced across groups.
    • Median follow-up of 33 months; complete primary endpoint ascertainment for 99.2% of follow-up.
  • Primary Outcome Results:
    • Ticagrelor 90 mg: 7.85% vs. Placebo: 9.04% (HR 0.85; 95% CI, 0.75–0.96; P=0.008)
    • Ticagrelor 60 mg: 7.77% vs. Placebo: 9.04% (HR 0.84; 95% CI, 0.74–0.95; P=0.004)
  • Secondary Outcome Results:
    • Reduction in myocardial infarction with both ticagrelor doses.
    • Reduction in stroke with ticagrelor 60 mg.
    • No significant difference in all-cause mortality.
  • Subgroup Analyses: Efficacy consistent across major subgroups (age, sex, race, etc.).
  • Adverse Events/Safety Data:
    • TIMI Major Bleeding:
      • Ticagrelor 90 mg: 2.60%
      • Ticagrelor 60 mg: 2.30%
      • Placebo: 1.06% (P<0.001 for both doses vs. placebo)
    • Fatal Bleeding/Internal Hemorrhage: No significant differences.
    • Dyspnea: Increased with ticagrelor (90 mg: 18.93%; 60 mg: 15.84%) vs. placebo (6.38%).
Outcome Intervention Group Control Group Difference (95% CI) P-value
Primary Outcome 7.85% (90 mg) 9.04% (Placebo) -1.19% (−2.06 to −0.33) 0.008
7.77% (60 mg) 9.04% (Placebo) -1.27% (−2.22 to −0.35) 0.004
TIMI Major Bleeding 2.60% (90 mg) 1.06% (Placebo) +1.54% (1.20 to 1.88) <0.001
2.30% (60 mg) 1.06% (Placebo) +1.24% (0.93 to 1.55) <0.001
Dyspnea 18.93% (90 mg) 6.38% (Placebo) +12.55% <0.001
15.84% (60 mg) 6.38% (Placebo) +9.46% <0.001

Authors' Conclusions

  • Ticagrelor at doses of 90 mg or 60 mg twice daily added to low-dose aspirin significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke in post-MI patients 1 to 3 years previously.
  • The benefit of ticagrelor was associated with an increased risk of TIMI major bleeding.
  • Findings support the use of long-term ticagrelor for secondary prevention in high-risk post-MI patients, balancing ischemic benefits against bleeding risks.

Critical Analysis

A. Strengths

  • Large Sample Size: Included over 21,000 patients, enhancing power and generalizability of findings.
  • Randomized, Double-Blind Design: Minimizes biases, ensuring robust internal validity.
  • Diverse Population: Conducted across 31 countries, improving applicability to various healthcare settings.
  • Comprehensive Outcome Assessment: High follow-up adherence with 99.2% endpoint ascertainment.
  • Pre-Specified Outcomes and Analysis: Reduces the risk of data dredging, supporting results' reliability.
  • Independent Data Analysis: Conducted by the TIMI Study Group, enhancing credibility.

B. Limitations

  • Increased Bleeding Risk: May limit applicability in patients at elevated bleeding risk.
  • Exclusion Criteria: Excluded patients with recent bleeding, stroke, or on anticoagulants, limiting generalizability.
  • High Discontinuation Rates: Approximately 32% in the 90 mg group and 28.7% in the 60 mg group discontinued therapy prematurely.
  • Subgroup Analysis Caveats: While efficacy consistent, may not detect differences within smaller subgroups.
  • No Significant Mortality Benefit: Composite endpoints improved, but all-cause mortality did not differ significantly.

Literature Review

A. Positioning the Current Study in Existing Evidence

The PEGASUS-TIMI 54 trial by Bonaca et al. (2015) explores extended ticagrelor therapy beyond the conventional one-year period for post-MI patients. Standard care previously recommended DAPT for up to one year.

Key Previous Studies:

  • PLATO Trial (Wallentin et al., 2009): Demonstrated ticagrelor's superiority over clopidogrel in ACS patients.
  • DAPT Trial (Mega et al., 2011): Showed extended DAPT reduced ischemic events but increased bleeding.
  • GRAPE Registry (Alexopoulos et al., 2016): Compared real-world antiplatelet therapies, highlighting bleeding and efficacy differences.
  • GLOBAL LEADERS Trial (Tomaniak et al., 2020): Explored ticagrelor monotherapy post-DAPT in various populations.

Methodological Quality Comparison:

  • PEGASUS-TIMI 54: Extensive sample size and multinational study.
  • PLATO: Direct comparison to clopidogrel; PEGASUS used placebo.
  • DAPT and GRAPE: Offer real-world insights with varying comparator durations or agents.

Guidelines and Consensus Statements:

  • AHA 2019: Emphasizes tailored therapy, especially differentiating MI types.
  • ESC Guidelines: Initially recommended up to one year of DAPT.

Geographic and Population Differences:

  • PEGASUS-TIMI 54's multinational design enhances its applicability.
  • Studies like GRAPE provide context-specific insights for different regions.

B. Comprehensive Synthesis of Findings

  • Alignment with Recent Data: PEGASUS aligns with PLATO on ticagrelor's efficacy.
  • Strengths and Weaknesses of Referenced Studies: Each study provides unique insights but varies in approach and focus.
  • Clinical Applicability: Evidence supports extended DAPT in high-risk patients.
  • Integration of Meta-Analyses: Confirms ticagrelor's consistent benefit with bleeding risks.
  • Cost-Effectiveness: Extended ticagrelor may increase medication costs, requires careful monitoring.

C. Gaps and Future Directions

  • Unanswered Questions: Optimal duration beyond three years; safety in excluded populations.
  • Future Research Areas: Evaluating specific subgroups, understanding ticagrelor's mechanism.

Clinical Application

  • Extended ticagrelor therapy may be considered for high-risk post-MI patients, especially those with multiple risk factors.
  • Careful assessment of bleeding risks is essential before initiating therapy, aligning with evolving guidelines.

How To Use This Info In Practice

Clinicians should balance ticagrelor's proven reduction in major cardiovascular events against increased bleeding risks, integrating the therapy into evidence-based guidelines and patient-specific protocols.