PEGASUS - Long-term ticagrelor in patients with prior MI

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Bonaca MP, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.

Bottom line: In patients with prior MI >1 year ago + 1 additional CV risk factor, ticagrelor 60 mg PO BID reduced the risk of MI (NNT 125) & stroke (NNT 250) over 2-3 years, though this was offset by an increased risk of adverse events, including major bleed (NNH 84), dyspnea (NNH 11) and gout attacks (NNH 200).

The "full PLATO" dose of 90 mg BID further increased the risk of adverse events without increasing efficacy over the 60 mg BID dose.

 

    Patients (n=21,162)

    • Inclusion
      • Age 50+ years
      • MI 1-3 y before enrollment
      • 1 or more additional risk factors:
        • Age 65+ years
        • >1 prior MI
        • Multivessel CAD
        • CKD with eGFR <60
        • Diabetes (requiring meds)
    • Exclusion
      • Prior ischemic stroke, intracranial hemorrhage, CNS tumor, intracranial vascular abnormality (e.g. AVM, aneurysm)
      • Prior GI bleed within 6 months
      • Major surgery in past 30 days
      • Bleeding disorder
      • Planned use of oral anticoagulant, P2Y12 inhibitor, dipyridamole, or cilostazol
    • "Average" patient
      • Age 65 y
      • Female 24%
      • White 86%
      • CV history
        • 1.7 y since last MI
        • >1 prior MI 16%
        • Multivessel CAD 59%
        • Prior PCI 83%
        • PAD 5%
      • CV risk factors
        • Current smoker 17%
        • HTN 78%
        • CKD (eGFR <60) 23%
        • Dyslipidemia 77%
        • Diabetes 32%

    Interventions

    • I 1: Ticagrelor 90 mg PO BID (PLATO dose)
    • I 2: Ticagrelor 60 mg PO BID (reduced dose)
    • Control: Placebo
    • Co-interventions:
      • ASA 75-150 mg PO daily 100%
      • Statin 93%
      • ACEI/ARB 80%
      • Beta-blocker 83%

    Results @ mean 2.75 years

    • Efficacy
      • Death from any cause: Ticag90 5.2%, ticag60 4.7%, placebo 5.2%
        • Ticag90 vs placebo: Hazard ratio (HR) 1.00 (95% confidence interval 0.86-1.16)
        • Ticag60 vs placebo: HR 0.89 (0.76-1.04)
      • Primary outcome (CV death, MI or stroke): Ticag90 7.8%, ticag60 7.8%, placebo 9.0%
        • Ticag90 vs placebo: HR 0.85 (0.75-0.96; NNT 85)
        • Ticag60 vs placebo: HR 0.84 (0.74-0.95; NNT 85)
      • MI: 4.4% vs 4.5% vs 5.3%
        • Ticag90 vs placebo: HR 0.81 (0.69-0.95, NNT 112)
        • Ticag60 vs placebo: HR 0.84 (0.72-0.98, NNT 125)
      • Any stroke: 1.6% vs 1.5% vs 1.9%
        • Ticag90 vs placebo: HR 0.82 (0.63-1.07)
        • Ticag60 vs placebo: HR 0.75 (0.57-0.98; NNT 250)
    • Safety
      • Premature discontinuation: 32.0% vs 28.7% vs 21.4% (NNH 11 & 14, respectively) 
      • Major bleed (TIMI definition): 2.6% vs 2.3% vs 1.1%
        • Ticag90 vs placebo: HR 2.69 (1.96-3.70; NNH 67)
        • Ticag60 vs placebo: HR 2.32 (1.68-3.21; NNH 84)
      • Dyspnea: 18.9% vs 15.8% vs 6.4%
        • Ticag90 vs placebo: HR 3.55 (3.16-3.98; NNH 8)
        • Ticag60 vs placebo: HR 2.81 (2.50-3.17; NNH 11)
        • Severe dyspnea: 0.4% vs 0.4% vs 0.1%
      • Gout: 2.3% vs 2.0% vs 1.5%
        • Ticag90 vs placebo: HR 1.77 (1.32-2.37; NNH 125)
        • Ticag60 vs placebo: HR 1.48 (1.10-2.00; NNH 200)

    Issues with internal validity?

    • No: Randomized, allocation-concealed, double-blind trial with low loss-to-follow-up (~1%) analyzed using the intention-to-treat population

    Additional PEGASUS publications

    • A secondary analysis evaluated the impact of timing of enrolment into PEGASUS relative to previous P2Y12 inhibitor use
      • Test for interaction p<0.001 for primary outcome, no difference in relative risk increase of bleeding
        • Greatest relative risk reduction seen for those within 30 days of previous P2Y12 inhibitor use (HR 0.73, 0.61-0.87 for either ticagrelor dose vs placebo)
          • Primary outcome @ 3 years: Ticagrelor 7.7%, placebo 9.9% (NNT 46)
          • TIMI major bleeding @ 3 years: Ticagrelor 2.5%, placebo 0.7% (NNH 56)
        • No statistically significant benefit in those who discontinued P2Y12 inhibitor 30-365 days before PEGASUS (HR 0.86, 0.71-1.04) & >1 year before pegasus (HR 1.01, 0.80-1.27)
      • Despite a greater relative & absolute risk reduction in those with P2Y12 inhibitor discontinuation <30 days prior to PEGASUS enrolment, ischemic benefit still mostly offset by increased risk of major bleed