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Randomized Controlled Trial
. 2021 Feb 16;10(4):e017008.
doi: 10.1161/JAHA.120.017008. Epub 2021 Feb 9.

Predictors, Type, and Impact of Bleeding on the Net Clinical Benefit of Long-Term Ticagrelor in Stable Patients With Prior Myocardial Infarction

Giulia Magnani  1 , Diego Ardissino  1 , KyungAh Im  2 , Andrzej Budaj  3 , Robert F Storey  4 , P Gabriel Steg  5 , Deepak L Bhatt  2 , Marc Cohen  6 , Ton Oude Ophius  7 , Assen Goudev  8 , Alexander Parkhomenko  9 , Gabriel Kamensky  10 , Dominick J Angiolillo  11 , José López-Sendón  12 , Per Johanson  13 , Eugene Braunwald  2 , Marc S Sabatine  2 , Marc P Bonaca  14
Affiliations
Randomized Controlled Trial

Predictors, Type, and Impact of Bleeding on the Net Clinical Benefit of Long-Term Ticagrelor in Stable Patients With Prior Myocardial Infarction

Giulia Magnani et al. J Am Heart Assoc. .

Abstract

Background Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. Methods and Results 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) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long-term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3-fold higher rates of bleeding with ticagrelor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; P=0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65-0.96; P interaction = 0.03). Conclusions In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor. Registration URL https://www.clinicaltrials.gov/. Unique identifier: NCT01225562.

Keywords: benefit‐risk ratio; bleeding; long‐term ticagrelor; myocardial infarction.

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Conflict of interest statement

The TIMI Study Group has received significant research grant support from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Giulia Magnani reports speaking fees from AstraZeneca, Daiichi Sankyo, consultancy fee from Boehringer Ingelheim. KyungAh Im is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. Andrej Budaj reports personal fees and non‐financial support from AstraZeneca, during the conduct of the study; personal fees and non‐financial support from Bristol Myers Squibb/Pfizer, personal fees and non‐financial support from Bayer, personal fees and nonfinancial support from Sanofi Aventis, personal fees from Eisai, personal fees from Novartis, and personal fees from GlaxoSmithKline, outside the submitted work. Robert F Storey reports research grants, consultancy fees and honoraria from AstraZeneca; research grants and consultancy fees from PlaqueTec; consultancy fees and honoraria from Bayer; consultancy fees and honoraria from Bristol Myers Squibb/Pfizer alliance; and consultancy fees from Avacta, Idorsia, Haemonetics, Novartis, and Thromboserin. P. Gabriel Steg reports research grants from Amarin, Bayer, Merck, Sanofi, and Servier; and speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer‐Ingelheim, Bristol‐Myers‐Squibb, Idorsia, Lilly, Merck, Novartis, Novo‐Nordisk, Pfizer, Regeneron, Sanofi, and Servier. Deepak L. Bhatt reports the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the [Portico Re‐sheathable Transcatheter Aortic Valve System US IDE Trial, PORTICO] trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the [Efficacy of Secukinumab Compared to Adalimumab in Patients with Psoriatic Arthritis, ExCEED] trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the [Edoxaban versus standard of care and their effects on clinical outcomes in patients having undergone transcatheter aortic valve implantation, ENVISAGE] trial, funded by Daiichi Sankyo), Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; [Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention, RE‐DUAL] PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (editor‐in‐chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (editor‐in‐chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (deputy editor), [National Cardiovascular Data Registry ACTION, NCDR‐ACTION] Registry Steering Committee (chair), [VA‐Cardiovascular Assessment Reporting and Tracking, VA CART] Research and Publications Committee (chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; royalties: Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site coinvestigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. Marc Cohen reports grants and personal fees from AstraZeneca, during the conduct of the study; personal fees from Merck, Janssen, Maquet, BMS/Pfizer, Janssen, BI, Lilly, and malpractice attorneys; and grants from Janssen and Edwards, outside the submitted work. Ton Oude Ophius reports speaker fees from AstraZeneca and Amgen and has received grant support from Medtronic and Abbott. Assen Goudev reports speaker honoraria from and served on the advisory board for AstraZeneca. Alexander Parkhomenko reports research grants and honoraria from AstraZeneca, Bristol Myers Squibb/Pfizer alliance, Bayer, Amgen, Amarin, Sanofi Aventis, Servier, and Janssen. Gabriel Kamensky participated in the PEGASUS‐TIMI 54 trial supported by AstraZeneca. Dominick J. Angiolillo reports receiving payments as an individual for (1) consulting fee or honorarium from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol‐Myers Squibb, Chiesi, Daiichi‐Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; and (2) participation in review activities from CeloNova and St. Jude Medical. Institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi‐Sankyo, Eisai, Eli‐Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. Per Johanson is an employee of AstraZeneca. Eugene Braunwald reports grant support through Brigham and Women’s Hospital from AstraZeneca, Daiichi Sankyo, Merck, and Novartis; and consultancies with Amgen, Cardurion, MyoKardia, NovoNordisk, and Verve. Marc S. Sabatine reports research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, Critical Diagnostics, Daiichi‐Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research Development, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and Takeda (all >$10 000 per year); and consulting for Alnylam, Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol‐Myers Squibb, Cubist, CVS Caremark, Esperion, Intarcia, Ionis, The Medicines Company, MedImmune, Merck, MyoKardia, and Zeus Scientific (all ≤$10 000 per year except Amgen, Esperion, and Ionis). Marc P. Bonaca reports consulting for Aralez, Amgen, AstraZeneca, Bayer, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi. He is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from AstraZeneca.

Figures

Figure 1
Figure 1
TIMI major or minor bleeding by etiology (A) and site of spontaneous bleeding (B) in the overall safety population. TIMI indicates Thrombolysis in Myocardial Infarction.
Figure 2
Figure 2
Incidence and cause of mortality among patients who experienced a TIMI major or minor bleeding (overall safety cohort). TIMI indicates Thrombolysis in Myocardial Infarction.
Figure 3
Figure 3. Etiologies (A) and sites (B) of TIMI major or minor bleeding, Ticagrelor 60 mg vs. placebo.
ARI indicates absolute risk increase; HR, hazard ratio, KM, Kaplan–Maier; NA, not applicable; and TIMI, Thrombolysis in Myocardial Infarction.
Figure 4
Figure 4. Bleeding and death, ticagrelor 60 mg vs placebo.
HR indicates hazard ratio; KM, Kaplan–Maier; and TIMI, Thrombolysis in Myocardial Infarction.
Figure 5
Figure 5. TIMI major or minor bleeding in ticagrelor 60 mg vs placebo group stratified by low (N=11 240) or high (N=2714) bleeding risk at baseline.
A sensitivity analysis of safety was performed based on baseline bleeding risk, defined as the presence or absence of either a history of spontaneous bleeding requiring hospitalization before the randomization or anemia (defined as hemoglobin ≤13.5 g/dL for men and ≤12.0 g/dL for women). ARI indicates absolute risk increase; HR, hazard ratio; KM, Kaplan–Maier; and TIMI, Thrombolysis in Myocardial Infarction.
Figure 6
Figure 6. Efficacy and safety of ticagrelor 60 mg vs placebo stratified by high (N=2714) or low (N=11 240) bleeding risk at baseline.
A sensitivity analysis of efficacy and safety was performed based on baseline bleeding risk, defined as the presence or absence of either a history of spontaneous bleeding requiring hospitalization before the randomization or anemia (defined as hemoglobin ≤13.5 g/dL for men and ≤12.0 g/dL for women). ARI indicates absolute risk increase; ARR, absolute risk difference; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction, ICH, intracranial hemorrhage; and TIMI, Thrombolysis in Myocardial Infarction.
See this image and copyright information in PMC

Comment in

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