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

Dec 18, 2019
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Presenter/Author:
Marc P. Bonaca, MD, FACC
Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
AstraZeneca
Date Presented:
08/30/2016
Date Published:
12/07/2019
Date Updated:
12/18/2019
Original Posted Date:
03/14/2015
References

Contribution To Literature:

The PEGASUS-TIMI 54 trial showed that among aspirin-treated individuals with prior MI, ticagrelor reduced cardiovascular events.

Description:

The goal of the trial was to evaluate treatment with ticagrelor compared with placebo among subjects with a prior myocardial infarction (MI) on a background of aspirin therapy.

Study Design

  • Parallel
  • Randomized
  • Placebo
  • Blinded

Subjects with a history of MI (1-3 years prior) on aspirin therapy were randomized to ticagrelor 90 mg bid (n = 7,050) or ticagrelor 60 mg bid (n = 7,045) versus placebo (n = 7,067).

Patient population:

  • Total number of enrollees: 21,162
  • Duration of follow-up: median 33 months
  • Mean patient age: 65 years
  • Percentage female: 24%
  • Percentage diabetics: 32%
  • History of percutaneous coronary intervention: 83%
  • Median time from qualifying MI: 1.7 years
  • History of ST-segment elevation MI (STEMI): 53%
  • History of non-STEMI: 41%

Inclusion criteria:

Subjects at least 50 years of age with at least one of the following:

  • Age ≥65 years
  • Diabetes
  • Second MI (>1 year ago)
  • Multivessel coronary disease
  • Creatinine clearance <60 cc/min

Exclusion criteria:

  • Planned use of an ADP antagonist
  • Bleeding disorder
  • History of ischemic stroke, intracranial hemorrhage, central nervous system tumor, or vascular abnormality
  • Recent gastrointestinal bleed or major surgery
  • At risk for bradycardia
  • Dialysis or severe liver disease

Principal Findings:

The primary outcome of cardiovascular death, MI, or stroke occurred in 7.8% of the ticagrelor 90 mg bid group (hazard ratio [HR] vs. placebo = 0.85, p = 0.008), 7.8% of the ticagrelor 60 mg bid group (HR vs. placebo = 0.84, p = 0.004), and 9.0% of the placebo group. This translates into 83 individuals who need to be treated to prevent one adverse event. The association of ticagrelor on the primary outcome was the same in all tested subgroups.

Secondary outcomes:

  • TIMI major bleeding: 2.6% with ticagrelor 90 mg (HR vs. placebo = 2.7, p < 0.001), 2.3% with ticagrelor 60 mg (HR vs. placebo = 2.3, p < 0.001), and 1.1% with placebo
  • Intracranial hemorrhage: 0.6% with ticagrelor 90 mg, 0.6% with ticagrelor 60 mg, and 0.5% with placebo (p = NS for either group vs. placebo)
  • All-cause mortality: 5.2% with ticagrelor 90 mg, 4.7% with ticagrelor 60 mg, and 5.2% with placebo (p = 0.99 for ticagrelor 90 mg vs. placebo and p = 0.14 for ticagrelor 60 mg vs. placebo)
  • MI: 4.4% with ticagrelor 90 mg (HR vs. placebo = 0.81, p = 0.01), 4.5% with ticagrelor 60 mg (HR vs. placebo = 0.84, p = 0.03), and 5.3% with placebo
  • All stroke: 1.5% with ticagrelor 60 mg versus 1.9% with placebo (p = 0.034)
  • Ischemic stroke: 1.3% with ticagrelor 60 mg versus 1.7% with placebo (p = 0.063)
  • Dyspnea adverse event: 18.9% with ticagrelor 90 mg, 15.8% with ticagrelor 60 mg, and 6.4% with placebo (p < 0.01 for either group vs. placebo)
  • Total costs: $10,016 with ticagrelor 60 mg versus $2,333 with placebo (p < 0.001). Cost-effectiveness for ticagrelor was enhanced when there was >1 prior MI, multivessel disease, diabetes, renal dysfunction, age <75 years, and peripheral artery disease.

Multivessel coronary disease: A total of 59.4% of patients had multivessel coronary artery disease. Among these, ticagrelor was associated with a reduction in major adverse cardiac events (HR 0.82, p = 0.004) and coronary events (HR 0.76, p < 0.0001). Ticagrelor was associated with an increase in major bleeding (HR 2.67, p < 0.0001), but not intracranial hemorrhage.

Coronary stent (n = 16,891) vs. no coronary stent (n = 4,199):

  • Cardiovascular death, MI, or stroke among those with no prior coronary stent: 11.1% with ticagrelor vs. 13.2% with placebo (HR 0.82, p = 0.04)
  • Cardiovascular death, MI, or stroke among those with prior coronary stent: 7.0% with ticagrelor vs. 8.0% with placebo (HR 0.85, p = 0.009; p for interaction = 0.76)
  • MI among those with no prior coronary stent: 4.8% with ticagrelor vs. 5.6% with placebo (HR 0.86, p = 0.33)
  • MI among those with prior coronary stent: 4.4% with ticagrelor vs. 5.2% with placebo (HR 0.81, p = 0.008; p for interaction = 0.74)

Interpretation:

Among patients with prior MI on aspirin therapy, the addition of ticagrelor was beneficial. Ticagrelor compared with placebo reduced the risk of cardiovascular death, MI, or stroke. All-cause and cardiovascular mortality were similar between the groups. Ticagrelor was also associated with an increase in TIMI major bleeding, but was not associated with an increase in intracranial hemorrhage.

Efficacy and safety were similar among those with multivessel coronary artery disease and history of coronary stent vs. no coronary stent. The two doses of ticagrelor resulted in a similar degree of efficacy (adverse cardiovascular events) and safety (bleeding). Ticagrelor 60 mg twice daily was associated with a reduction in stroke (ischemic stroke) compared with placebo. Cost-effectiveness for ticagrelor could be enhanced if certain high-risk characteristics were present.

References:

Furtado RH, Nicolau JC, Magnani G, et al. Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54. Eur Heart J 2019;Dec 7:[Epub ahead of print].

Bansilal S, Bonaca MP, Cornel JH, et al. Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease. J Am Coll Cardiol 2018;71:489-96.

Magnuson EA, Li H, Wang K, et al. Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction: Results From the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol 2017;70:527-38.

Bonaca MP, Goto S, Bhatt DL, et al. Prevention of Stroke With Ticagrelor in Patients With Prior Myocardial Infarction: Insights From PEGASUS-TIMI 54 (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). Circulation 2016;Aug 30:[Epub ahead of print].

Presented by Dr. Marc Bonaca at the European Society of Cardiology Congress, Rome, Italy, August 30, 2016.

Bonaca MP, Bhatt DL, Cohen M, et al., on behalf of the PEGASUS-TIMI 54 Steering Committee and Investigators.  Long-Term Use of Ticagrelor in Patients With Prior Myocardial Infarction. N Engl J Med 2015;Mar 14:[Epub ahead of print].

Editorial Comment: Keaney JF Jr. Balancing the Risks and Benefits of Dual Platelet Inhibition. N Engl J Med 2015;Mar 14:[Epub ahead of print]. 

Presented by Dr. Marc Steven Sabatine at ACC.15, San Diego, CA, March 14, 2015.

Bonaca MP, Bhatt DL, Braunwald E, et al. Design and rationale for the 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. Am Heart J 2014;167:437-44.e5.

Clinical Topics: Acute Coronary Syndromes, Prevention, Atherosclerotic Disease (CAD/PAD)

Keywords: ACC Annual Scientific Session, Acute Coronary Syndrome, Adenosine, Aspirin, Coronary Artery Disease, Incidence, Myocardial Infarction, Purinergic P2Y Receptor Antagonists, Secondary Prevention, Stroke, omega-Chloroacetophenone, ESC Congress


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