PEGASUS-TIMI 54

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Bonaca MP, et al. "Long-term use of ticagrelor in patients with prior myocardial infarction". The New England Journal of Medicine. 2015. 372(19):1791-1800.
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Clinical Question

In patients who had an MI in the prior 1-3 years, does ticagrelor+ASA reduce the risk of cardiovascular death, myocardial infarction, or stroke as compared to placebo?

Bottom Line

In patients who had prior MI 1-3 years earlier, ticagrelor (90 mg or 60 mg, twice daily) in combination with ASA significantly reduced the risk of cardiovascular death, MI, or stroke. However, the risk of TIMI major and minor bleeding are significantly increased.

Major Points

Ticagrelor is a reversible P2Y12 receptor antagonist which has been reported to be more effective and more rapid in inhibiting platelet aggregation as compared to clopidogrel.[1]

Published 2015, 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 randomized 21,162 patients who had prior MI 1-3 years earlier to receive ticagrelor (90 mg or 60 mg, twice daily) or placebo. All patients also received ASA. The study showed that ticagrelor (90 mg or 60 mg, twice daily dose) significantly reduced the risk of cardiovascular death, MI, or stroke. However, the risk of TIMI major and minor bleeding are significantly increased. It is important to note that patients in the trial were at a high risk of ischemic events and those with recent bleeding or requirement for oral anticoagulants were excluded.

Another study on ticagrelor is the PLATO.[2] The study reported that ticagrelor reduced the rate of death from vascular causes, MI, or stroke in patients who have an acute coronary syndrome as compared to clopidogrel. Extended therapy with aspirin and clopidogrel after MI was explored in DAPT.

Guidelines

ACC/AHA DAPT in CAD (2016, adapted)[3]

  • The dose of ASA 81 mg recommended in DAPT (COR I, LOE B-NR)
  • If stable ischemic heart disease treated with PCI:
    • If BMS, treat with DAPT, including a P2Y12 inhibitor for ≥1 month (COR I, LOE A)
    • If DES, treat with DAPT, including a P2Y12 inhibitor for ≥6 months (COR I, LOE B-R)
    • If BMS or DES and good tolerance of DAPT and not high bleeding risk, continuing DAPT beyond the 1 or 6 month duration may be reasonable (COR IIb, LOE A)
    • If DES and high-risk for bleeding, high risk for bleeding complication (major intracranial surgery), or significant overt bleeding, discontinuation of P2Y12 after 3 mo may be reasonable (COR IIB, LOE C-LD)
  • If ACS treated with PCI:
    • If BMS or DES, treat with DAPT, including a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) for ≥12 mo (COR I, LOE B-R)
      • Ticagrelor may be preferable to clopidogrel for maintenance P2Y12 inhibitor therapy (COR IIa, LOE B-R)
      • If not at a high risk for bleeding complications and no history of stroke/TIA, it is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 inhibitor therapy (COR IIa, LOE B-R)
    • If coronary stent placed, tolerance of DAPT, no bleeding complications, no elevated risk of bleeding, continuation of DAPT for >12 mo may be reasonable (COR IIb, LOE A)
    • If DES placed and on DAPT, those with high risk of bleeding (e.g., oral anticoagulants), high risk for bleeding complication (major intracranial surgery), or significant overt bleeding, discontinuation of P2Y12 inhibitor therapy after 6 mo may be reasonable (COR IIb, LOE C-LD)
    • Do not give prasugrel if history of stroke/TIA (COR III/harm, LOE B-R)

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=21,162
    • Ticagrelor orally, 90 mg twice daily (n=7,050)
    • Ticagrelor orally, 60 mg twice daily (n=7,045)
    • Placebo (n=7,067)
  • Setting: 1,161 centers in 31 countries
  • Enrollment: 2010-2013
  • Median follow-up: 33 months
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, MI, or stroke

Population

Inclusion Criteria

  • MI 1-3 years prior to enrollment
  • Age ≥50 years
  • ≥1 of the following:
    • Age ≥65 years
    • DM requiring medication
    • Second prior MI
    • Multivessel CAD
    • CKD with creatinine clearance <60 mL/min

Exclusion Criteria

  • Planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period
  • Bleeding disorder
  • Prior ischemic stroke, intracranial bleeding, CNS tumor, or an intracranial vascular abnormality
  • GI bleed in prior 6 months
  • Major surgery in prior 30 days

Baseline Characteristics

From the ticagrelor 90 mg group

  • Demographics: Age 65 years, 24% female, 87% white race
  • Weight: 82.0±16.7 kg
  • PMH: HTN 78%, HLD 77%, active smoker 17%, DM 32%, multivessel CAD 59%, prior PCI 83%, >1 previous MI 16%, CKD (eGFR<60 ml/min/1.73 m2) 24%, PAD 5%
  • Medications: Aspirin 99.8%, statin 93%, beta-blocker 82%, ACE-inhibitor or ARB 81%
  • Qualifying event specifics:
    • Years since MI: 1.7
    • Type: STEMI 53%, NSTEMI 41%, unknown 5%

Interventions

  • Patients were randomly assigned, in a 1:1:1 ratio within each center, to receive oral ticagrelor 90 mg twice daily, oral ticagrelor 60 mg twice daily, or placebo
  • All patients were advised to take aspirin 75 to 150 mg daily
  • If a patient in either group developed an indication for P2Y12 receptor blockade, a modified double-blind, double-dummy treatment was used instead

Ticagrelor group[4]

  • Patients received ticagrelor 90 mg or 60 mg twice daily
  • The dose 90 mg twice daily was selected based on the PLATO trial[2]
  • If a patient in this group developed an indication for P2Y12 receptor blockade, a modified study treatment option is used to assign patients to receive 180 mg loading dose followed by 90 mg twice daily, based on the dosing used in the PLATO trial

Placebo group

  • If a patient in this group developed an indication for P2Y12 receptor blockade, they received clopidogrel

Outcomes

Primary Outcomes

CV mortality, MI, or stroke at 3 years
Comparisons are ticagrelor 90 mg vs. placebo
7.85% vs. 9.04% (HR 0.85; 95% CI 0.75-0.96; P=0.008)
Comparisons are ticagrelor 60 mg vs. placebo
7.77% vs. 9.04% (HR 0.84; 95% CI 0.74-0.95; P=0.004)

Secondary Outcomes

CV mortality
Comparisons are ticagrelor 90 mg vs. placebo
2.94% vs. 3.39% (HR 0.87; 95% CI 0.71-1.06; P=0.15)
Comparisons are ticagrelor 60 mg vs. placebo
2.86% vs. 3.39% (HR 0.83; 95% CI 0.68-1.01; P=0.07)
All-cause mortality
Comparisons are ticagrelor 90 mg vs. placebo
5.15% vs. 5.16% (HR 1.00; 95% CI 0.86-1.16; P=0.99)
Comparisons are ticagrelor 60 mg vs. placebo
4.69% vs. 5.16% (HR 0.89; 95% CI 0.76-1.04; P=0.14)
CHD mortality, MI, or stroke
Comparisons are ticagrelor 90 mg vs. placebo
6.99% vs. 8.33% (HR 0.82; 95% CI 0.72-0.93; P=0.002)
Comparisons are ticagrelor 60 mg vs. placebo
7.09% vs. 8.33% (HR 0.83; 95% CI 0.73-0.94; P=0.003)
MI
Comparisons are ticagrelor 90 mg vs. placebo
4.40% vs. 5.25% (HR 0.81; 95% CI 0.69-0.95; P=0.01)
Comparisons are ticagrelor 60 mg vs. placebo
4.53% vs. 5.25% (HR 0.84; 95% CI 0.72-0.98; P=0.03)
CV mortality or MI
Comparisons are ticagrelor 90 mg vs. placebo
6.79% vs. 7.81% (HR 0.85; 95% CI 0.75-0.97; P=0.01)
Comparisons are ticagrelor 60 mg vs. placebo
6.77% vs. 7.81% (HR 0.85; 95% CI 0.74-0.96; P=0.01)
Stroke (all types)
Comparisons are ticagrelor 90 mg vs. placebo
1.61% vs. 1.94% (HR 0.82; 95% CI 0.63-1.07; P=0.14)
Comparisons are ticagrelor 60 mg vs. placebo
1.47% vs. 1.94% (HR 0.75; 95% CI 0.57-0.98; P=0.03)

Subgroup Analysis

No heterogeneity in the efficacy of ticagrelor (either dose) across major subgroups, including age, sex, race, weight, DM, CKD, multivessel CAD, type of index MI, history of PCI, and aspirin dose.

Adverse Events

TIMI major bleeding[5]
Comparisons are ticagrelor 90 mg vs. placebo
2.60% vs. 1.06% (HR 2.69; 95% CI 1.96-3.70; P<0.001)
Comparisons are ticagrelor 60 mg vs. placebo
2.30% vs. 1.06% (HR 2.32; 95% CI 1.68–3.21; P<0.001)
TIMI minor bleeding[5]
Comparisons are ticagrelor 90 mg vs. placebo
1.31% vs. 0.36% (HR 4.15; 95% CI 2.47-7.00; P<0.001)
Comparisons are ticagrelor 60 mg vs. placebo
1.18% vs. 0.36% (HR 3.31; 95% CI 1.94-5.63; P<0.001)
Dyspnea
Comparisons are ticagrelor 90 mg vs. placebo
18.93% vs. 6.38% (HR 3.55; 95% CI 3.16-3.98; P<0.001)
Comparisons are ticagrelor 60 mg vs. placebo
15.84% vs. 6.38% (HR 2.81; 95% CI 2.50-3.17; P<0.001)
Gout
Comparisons are ticagrelor 90 mg vs. placebo
2.28% vs. 1.51% (HR 1.77; 95% CI 1.32-2.37; P<0.001)
Comparisons are ticagrelor 60 mg vs. placebo
1.97% vs. 1.51% (HR 1.48; 95% CI 1.10-2.00; P=0.01)
Cancer-related deaths
Comparisons are ticagrelor 90 mg vs. placebo
1.10% vs. 0.76% (P not given)
Comparisons are ticagrelor 60 mg vs. placebo
0.92% vs. 0.76% (P not given)

Criticisms

  • Patients in the trial were at a high risk for ischemic events. Hence, patients at a low risk for ischemic events may not obtain as much benefit as seen in the trial.[6][7]
  • Patients with recent bleeding or requirement for oral anticoagulation were excluded. Therefore the benefits seen in the trial can not be applicable to patients with a high risk of bleeding.[6][7][8]
  • There's an increase in cancer-related deaths noted in patients who took ticagrelor (either dose). The significance of this is unclear.[9]

Funding

AstraZeneca, the manufacturers of Brilinta (the brand name for ticagrelor).

Further Reading

  1. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038-1047.
  2. 2.0 2.1 Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2009 Sep 10;361(11):1045–57.
  3. Template:Pmid:27026020
  4. 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;167:437,444.e5.
  5. 5.0 5.1 Rao SV, O’Grady K, Pieper KS, et al. A Comparison of the Clinical Impact of Bleeding Measured by Two Different Classifications Among Patients With Acute Coronary Syndromes. J Am Coll Cardiol. 2006;47(4):809-816. doi:10.1016/j.jacc.2005.09.060.
  6. 6.0 6.1 Keaney JF. Balancing the Risks and Benefits of Dual Platelet Inhibition. N Engl J Med. 2015;372(19):1854–6.
  7. 7.0 7.1 Alexopoulos D. Long-term ticagrelor therapy in patients with prior myocardial infarction significantly reduces ischaemic events, albeit with increased bleeding. Evid Based Med. 2015 Aug;20(4):132.
  8. Mearns BM. Antiplatelet therapy: Long-term ticagrelor use in patients with history of MI. Nat Rev Cardiol. 2015;12(5):260–260.
  9. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med. 2015;373:1271-1275