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American Heart Association Scientific Sessions 2018

American Heart Association Scientific Sessions 2018. Ticagrelor for long-term secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: Insights from PEGASUS-TIMI 54.

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American Heart Association Scientific Sessions 2018

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  1. American Heart Association Scientific Sessions 2018 Ticagrelor for long-term secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: Insights from PEGASUS-TIMI 54 Remo H. M. Furtado, DL Bhatt, PG Steg, M Cohen, RF Storey, KW Im, MS Sabatine, MP Bonaca On behalf of the PEGASUS-TIMI 54 Executive & Steering Committees and Investigators NCT00526474 Dec 2017

  2. Disclosures PEGASUS-TIMI 54 was funded by a grant from AstraZeneca to Brigham and Women’s Hospital Remo H. M. Furtado discloses: Research Grant* from AstraZeneca, DalCor, Boehinger, Pfizer, Bayer, Sanofi in the last 36 months. * Modest, received from my institution, for participation as PI/SI in industry-sponsored randomized clinical trials.

  3. CURE: DAPT with Clopidgrel after ACS No. at Risk No. at Risk Clopidogrel 6259 6145 6070 6026 5990 Placebo 6303 6159 6048 5993 5965 5981 5481 4742 4004 3180 2418 5954 5390 4639 3929 3159 2388 12,562 Patients with NSTEACS 60 % managed w/o revasc for index event CV Death, MI, or Stroke First 30 Days CV Death, MI, or Stroke >30 Days–1 Year 1.00 1.00 Clopidogrel Clopidogrel .98 .98 .96 .96 Placebo Placebo Proportion Event-Free Proportion Event-Free .94 .94 RRR: 21% 95% CI, 0.67–0.92 P=.003 RRR: 18% 95% CI, 0.70–0.95 P=.009 .92 .92 .90 .90 0 1 2 3 4 1 4 6 8 10 12 Month Week Yusuf S, et al. Circulation. 2003;107:966-972.

  4. Ticagrelor decreased MACE compared to clopidogrel irrespective of management strategy HR 0.85 (0.73 to 1.00) Non-invasive HR 0.84 (0.75 to 0.94) Invasive P for interaction = 0.89 14.3% 12.0% 10.6% 8.9% 1-. James SK et al. BMJ 2011; 342:d3527

  5. Long-Term Secondary Prevention with Prasugrel not Beneficial in Patients with Medically Managed ACS HR (95% CI) ≤ 1 Year: 0.99 (0.84, 1.16) HR (95% CI) > 1 Year: 0.72 (0.54, 0.97) Overall HR 0.91 (0.79, 1.05) P = 0.21 Interaction P = 0.07 However, In Subgroup of 3,085 pts with confirmed CAD (angio) there was benefit HR 0.77 (0.61 – 0.98) P=0.032 Wiviott SD et al. Lancet 2013 Roe MT et al. N Engl J Med 2012; 367:1297

  6. Long-Term Ticagrelor Reduces CVD/MI/Stroke in Patients with Prior MI Bonaca MP; Sabatine MS; et al. N Engl J Med 2015;372:1791

  7. Hypothesis • Patients with prior MI and no history of coronary stenting are at heightened long-term risk of recurrent spontaneous atherothrombosis • Even though they do not have coronary stents (no risk for stent thrombosis), due to their heightened risk of spontaneous events they will derive robust risk reductions from long-term ticagrelor

  8. Methods • History of PCI/Stent was collected at baseline and pre-specified as a subgroup for analysis • Ischemic risk compared based on PCI status with adjustment for baseline differences (Cox model) • Efficacy and safety of ticagrelor (pooled) evaluated by history of PCI

  9. Baseline Characteristics 72 patients had missing information regarding prior stenting status at baseline

  10. Event Rates in Placebo Arm Primary Endpoint - CV Death, MI or Stroke 15% 13.24% 10% 7.98% 5% Patients without prior stenting Patients with prior stenting 0% 0 360 720 1080 Days HR 1.65 (1.38 to 1.97) p < 0.0001

  11. Event Rates in Placebo Arm Adj* HR 2.74 Adj* p < 0.0001 Adj* HR 2.29 Adj* p < 0.0001 Adj* HR 1.50 Adj* p < 0.0001 *Adjusted model included following variables: age, sex, weight, hypertension, smoking, Diabetes Mellitus, Multivessel CAD, history of Second MI, eGFR<60 vs eGFR >=60, years from QE MI (<2yrs vs >=2 yrs, MI type (STEMI or not), Prior CABG and Region of the World

  12. Primary Endpoint by History of Coronary Stent P-interaction = 0.95 15 % Placebo – Without prior stenting 13.24% Placebo – With prior stenting Ticagrelor (pooled) – Without prior stenting Ticagrelor (pooled) – With prior stenting 11.10 % Ticagrelor in patients without prior stenting HR (95% CI) = HR 0.82 (0.68 to 0.99) p = 0.044 10 % 7.98% ARR 2.14% NNT = 47 CV Death, MI or Stroke at 3 Years (KM %) 6.96 % Ticagrelor in patients with prior stenting HR (95% CI) = 0.85 (0.75 to 0.96) p = 0.009 5 % ARR 1.02% NNT = 98 0 %

  13. Components of 1ry efficacy outcome according to stenting status P-value HR (95 % CI) P for interaction CV death 0.087 0.80 (0.62 to 1.03) 0.86 0.88 (0.7 to 1.11) 0.28 MI 0.86 (0.64 to 1.16) 0.33 0.94 0.81 (0.70 to 0.95) 0.008 Stroke 0.031 0.63 (0.41 to 0.96) 0.51 Without Prior stenting 0.85 (0.65 to 1.11) 0.23 With prior stenting 0.3 0.5 1.0 2.0 4.0 Placebo better Ticagrelor better

  14. CV death 15 % Placebo – Without prior stenting Placebo – With prior stenting Ticagrelor (pooled) – Without prior stenting Ticagrelor (pooled) – With prior stenting P for interaction = 0.86 10 % Patients without prior stenting HR 0.80 (0.62 to 1.03) p = 0.087 7.67 % 6.17 % 5 % Patients with prior stenting HR 0.88 (0.7 to 1.11) p = 0.28 2.28% 2.05 % 0 %

  15. Safety Endpoints - Bleeding according to prior stenting HR (95 % CI) 2.65 (1.9 to 3.68) P < 0.0001 HR (95 % CI) 1.93 (0.99 to 3.78) P = 0.054 HR (95 % CI) 1.38 (0.84 to 2.26) HR (95 % CI) 0.75 (0.30 to 1.86) Event Rate at 3 Years (KM%) P = 0.21 P = 0.53 ICH or Fatal Bleeding TIMI Major Bleeding P for interaction = 0.71 P for interaction = 0.51

  16. All-cause mortality P-interaction = 0.15 15 % Placebo – Without prior stenting Ticagrelor (pooled) – Without prior stenting Placebo – With prior stenting Ticagrelor (pooled) – With prior stenting 10.03 % 8.50 % 10 % Patients without prior stenting HR 0.79 (0.64 to 0.99) p = 0.036 Patients with prior stenting HR 1.04 (0.88 to 1.24) p = 0.65 5 % 4.00 % 3.90 % 0 %

  17. Summary • Patients with history of MI and no prior coronary stenting are at heightened long-term risk of recurrent atherothrombosis and cardiovascular mortality • Efficacy and safety of long-term ticagrelor in patients with prior MI is consistent regardless of history of coronary stenting • Due to their risk profile, prior MI patients without prior stenting in PEGASUS-TIMI 54 had robust ischemic risk reductions with long-term ticagrelor

  18. Conclusions • Medically managed patients with prior MI remain at elevated long-term risk (driven by de novo events) and should be considered for intensive secondary prevention with ticagrelor • These observations highlight that the benefits of long-term DAPT with ticagrelor are largely driven by reductions in spontaneous events related to patient risk rather than stent risk Take-home message: treat the patient, not the stent!

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