Article Identification

Authors: TIMI Study Group (Top 5 authors not specified)

Journal: New England Journal of Medicine (NEJM), 2015, Volume 373, Issue 16

Type of Study: Randomized, double-blind, placebo-controlled clinical trial

DOI/PMID: PMID: 25773268 | DOI: 10.1056/NEJMoa1500857

Quick Reference Summary

Key Findings: In patients 1 to 3 years post-myocardial infarction, ticagrelor at doses of 90 mg and 60 mg twice daily, when added to low-dose aspirin, significantly reduced the composite outcome of cardiovascular death, myocardial infarction, or stroke compared to placebo (7.85% and 7.77% vs. 9.04%; P=0.008 and P=0.004 respectively).

Primary Outcomes: Both ticagrelor doses significantly decreased major cardiovascular events but increased the risk of TIMI major bleeding (2.60% and 2.30% vs. 1.06%; P<0.001 for each dose).

Core Clinical Question

In patients with a history of myocardial infarction (Population), does ticagrelor at doses of 90 mg or 60 mg twice daily (Intervention) compared to placebo (Comparison), reduce the incidence of cardiovascular death, myocardial infarction, or stroke (Outcome)?

Background

Disease Overview

Myocardial infarction (MI) is a prevalent global condition, with nearly 8 million individuals in the United States alone having a history of MI, placing them at increased risk for recurrent ischemic events.

Prior Data

• Aspirin reduces ischemic events in both acute coronary syndrome patients and those in secondary prevention post-MI.
• Addition of P2Y₁₂ receptor antagonists to aspirin has been effective in reducing ischemic events within the first year after acute coronary syndrome.

Current Standard of Care

Guidelines recommend P2Y₁₂ receptor antagonists for up to 1 year post-MI.

Knowledge Gaps

The efficacy and safety of prolonged dual antiplatelet therapy beyond one year post-MI have not been established.

Study Rationale

To evaluate whether long-term ticagrelor therapy in addition to aspirin can further reduce major cardiovascular events in stable post-MI patients beyond the first year.

Methods Summary

Study Design: Randomized, double-blind, placebo-controlled clinical trial.

Setting and Time Period: 1,161 sites across 31 countries, from October 2010 through May 2013.

Population Characteristics: 21,162 patients aged ≥50 years with a history of spontaneous MI 1 to 3 years prior, and at least one additional high-risk feature (e.g., age ≥65, diabetes, second MI, multivessel disease, chronic renal dysfunction).

Inclusion/Exclusion Criteria: Included patients on low-dose aspirin; excluded those requiring other P2Y₁₂ antagonists, with bleeding disorders, recent GI bleeding, history of stroke, etc.

Intervention Details: Random assignment to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all alongside low-dose aspirin (75-150 mg daily).

Control/Comparison Group: Placebo group continued on aspirin alone.

Primary and Secondary Outcomes

• Primary Efficacy Endpoint: Composite of cardiovascular death, MI, or stroke.
• Primary Safety Endpoint: TIMI major bleeding.
• Secondary Endpoints: Cardiovascular death, all-cause death, and other exploratory endpoints.

Statistical Analysis Approach: Intention-to-treat analysis using Cox proportional-hazards models; Kaplan–Meier estimates for cumulative incidence; hierarchical testing for secondary endpoints.

Sample Size Calculations: 1,360 primary endpoint events required for ~90% power to detect a 20% relative risk reduction with the 90 mg dose.

Ethics and Funding: Approved by ethics committees at all sites; funded by AstraZeneca.

Detailed Results

Participant Flow and Demographics

• Total Patients Randomized: 21,162
• Discontinuation Rates: 32.0% (90 mg), 28.7% (60 mg), 21.4% (placebo) P<0.001
• Median Follow-up: 33 months
• Baseline Characteristics: Majority had prior percutaneous coronary intervention (83.0%) and multivessel coronary artery disease (59.4%).

Primary Outcome Results

Outcome	Ticagrelor 90 mg Twice Daily	Ticagrelor 60 mg Twice Daily	Placebo	Difference (95% CI)	P-value
Cardiovascular Death, MI, or Stroke	7.85%	7.77%	9.04%	-1.19% (-1.95% to -0.43%)	P=0.008 (90 mg) P=0.004 (60 mg)

Effect Sizes and Confidence Intervals

• 90 mg vs. Placebo: Hazard Ratio 0.85; 95% CI [0.75 to 0.96]; P=0.008
• 60 mg vs. Placebo: Hazard Ratio 0.84; 95% CI [0.74 to 0.95]; P=0.004

Secondary Outcomes

• Myocardial Infarction Reduction: Significant with both doses.
• Stroke Reduction: Significant with 60 mg dose.
• Death from Any Cause: No significant difference.

Safety Data

Safety Endpoint	Ticagrelor 90 mg Twice Daily	Ticagrelor 60 mg Twice Daily	Placebo	Difference (95% CI)	P-value
TIMI Major Bleeding	2.60%	2.30%	1.06%	+1.54% (+0.86% to +2.22%)	P<0.001
Dyspnea	18.93%	15.84%	6.38%	+12.55% (+12.07% to +13.03%)	P<0.001

Adverse Events

Increased dyspnea and gout with ticagrelor; no significant difference in renal or bradyarrhythmic events.

Authors’ Conclusions

Primary Conclusions: In post-myocardial infarction patients 1 to 3 years post-event, ticagrelor at both 90 mg and 60 mg twice daily, when added to low-dose aspirin, significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke.

Interpretation of Results: The benefits in reducing ischemic events were achieved at the expense of increased major bleeding risks.

Clinical Implications: Long-term ticagrelor therapy can be considered for secondary prevention in high-risk post-MI patients, balancing ischemic benefits against bleeding risks.

Future Research Recommendations: Further studies to optimize dosing strategies and identify patient subgroups who may benefit most with minimal bleeding risk.

Critical Analysis

A. Strengths

• Large Sample Size: 21,162 patients enhance the reliability of results.
• Randomized, Double-Blind Design: Minimizes bias and ensures internal validity.
• Long Follow-Up Period: Median of 33 months provides robust data on long-term effects.
• Comprehensive Outcome Measures: Assessed both efficacy and safety endpoints thoroughly.
• International Multicenter Approach: Enhances external validity across diverse populations.

B. Limitations

• High Discontinuation Rates: 21.4% to 32.0% may affect the interpretation of long-term adherence and outcomes.
• Increased Bleeding Risks: While major bleeding increased, fatal or intracranial hemorrhages did not, but the overall safety profile may limit use in certain populations.
• Generalizability Issues: Exclusion of patients with recent bleeding, prior stroke, or on anticoagulants limits applicability to broader, real-world populations.

C. Literature Context

Not explicitly provided in the article; therefore, literature comparisons are based on the discussion section.

Clinical Application

• Change in Current Practice: Ticagrelor can be considered for long-term secondary prevention in post-MI patients beyond the first year, particularly in those with high ischemic risk and acceptable bleeding risk.
• Specific Populations: Most applicable to stable patients 1 to 3 years post-MI with additional high-risk features (e.g., age ≥65, diabetes, multivessel disease).
• Implementation Considerations: Requires careful patient selection to balance ischemic benefits against bleeding risks; monitoring for dyspnea may be necessary to ensure adherence.

How to Use This Info in Practice

Practitioners should consider adding ticagrelor (60 mg or 90 mg twice daily) to aspirin for long-term secondary prevention in post-MI patients who are at high risk for ischemic events and have a low risk of significant bleeding.