De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials
- PMID: 39226909
- DOI: 10.1016/S0140-6736(24)01616-7
De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials
Abstract
Background: Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation.
Methods: A systematic review and individual patient data (IPD)-level meta-analysis of randomised trials with centrally adjudicated endpoints was performed to evaluate the comparative efficacy and safety of ticagrelor monotherapy (90 mg twice a day) after short-term DAPT (from 2 weeks to 3 months) versus 12-month DAPT in patients undergoing percutaneous coronary intervention with a coronary drug-eluting stent. Randomised trials comparing P2Y12 inhibitor monotherapy with DAPT after coronary revascularisation were searched in Ovid MEDLINE, Embase, and two websites (www.tctmd.com and www.escardio.org) from database inception up to May 20, 2024. Trials that included patients with an indication for long-term oral anticoagulants were excluded. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. The principal investigators of the eligible trials provided IPD by means of an anonymised electronic dataset. The three ranked coprimary endpoints were major adverse cardiovascular or cerebrovascular events (MACCE; a composite of all-cause death, myocardial infarction, or stroke) tested for non-inferiority in the per-protocol population; and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding and all-cause death tested for superiority in the intention-to-treat population. All outcomes are reported as Kaplan-Meier estimates. The non-inferiority was tested using a one-sided α of 0·025 with the prespecified non-inferiority margin of 1·15 (hazard ratio [HR] scale), followed by the ranked superiority testing at a two-sided α of 0·05. This study is registered with PROSPERO (CRD42024506083).
Findings: A total of 8361 unique citations were screened, of which 610 records were considered potentially eligible during the screening of titles and abstracts. Of these, six trials that randomly assigned patients to ticagrelor monotherapy or DAPT were identified. De-escalation took place a median of 78 days (IQR 31-92) after intervention, with a median duration of treatment of 334 days (329-365). Among 23 256 patients in the per-protocol population, MACCE occurred in 297 (Kaplan-Meier estimate 2·8%) with ticagrelor monotherapy and 332 (Kaplan-Meier estimate 3·2%) with DAPT (HR 0·91 [95% CI 0·78-1·07]; p=0·0039 for non-inferiority; τ2<0·0001). Among 24 407 patients in the intention-to-treat population, the risks of BARC 3 or 5 bleeding (Kaplan-Meier estimate 0·9% vs 2·1%; HR 0·43 [95% CI 0·34-0·54]; p<0·0001 for superiority; τ2=0·079) and all-cause death (Kaplan-Meier estimate 0·9% vs 1·2%; 0·76 [0·59-0·98]; p=0·034 for superiority; τ2<0·0001) were lower with ticagrelor monotherapy. Trial sequential analysis showed strong evidence of non-inferiority for MACCE and superiority for bleeding among the overall and ACS populations (the z-curve crossed the monitoring boundaries or the required information size without crossing the futility boundaries or approaching the null). The treatment effects were heterogeneous by sex for MACCE (p interaction=0·041) and all-cause death (p interaction=0·050), indicating a possible benefit in women with ticagrelor monotherapy, and by clinical presentation for bleeding (p interaction=0·022), indicating a benefit in ACS with ticagrelor monotherapy.
Interpretation: Our study found robust evidence that, compared with 12 months of DAPT, de-escalation to ticagrelor monotherapy does not increase ischaemic risk and reduces the risk of major bleeding, especially in patients with ACS. Ticagrelor monotherapy might also be associated with a mortality benefit, particularly among women, which warrants further investigation.
Funding: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale.
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Conflict of interest statement
Declaration of interests MV reports grants or contracts from Om Pharma and Concept Medical; consulting fees from Astrazeneca, Biotronik, Chiesi Pharma, Om Pharma, Abbott Vascular, Terumo, Concept Medical, Daiichi Sankyo, Idorsia, Novartis, Johnson & Johnson, Janssen, Alvimedica, and Vesalio; and support for attending meetings or travel from Edwards Lifesciences. FG reports participation in an advisory board for Sanofi. KC reports grants or contracts from the EU's Horizon 2020 Research and Innovation Program (under grant agreement number 825162); support for attending meetings or travel from ECTRIMS; and being employed by Johnson & Johnson in a summer PhD internship and by the Department of Clinical Research, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, the Department of Clinical Research is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organisations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of conflicts of interest see https://www.ctu.unibe.ch/research_projects/declaration_of_interest/index_eng.html. UB reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Amgen, Abbott Laboratories, and Boston Scientific; and payment for expert testimony. GWS reports grants or contracts from Shockwave, Biosense-Webster, Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Phillips, Vascular Dynamics, Pulnovo, V-wave, and PCORI (payments to Mount Sinai Hospital); consulting fees from Abbott, Daiichi Sankyo, Ablative Solutions, CorFlow, Cardiomech, Robocath, Miracor, Vectorious, Abiomed, Valfix, Apollo Therapeutics, Elucid Bio, Cardiac Success, TherOx, HeartFlow, Neovasc, Ancora, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, HighLife, Elixir, Remote Cardiac Enablement, and Aria (personal payments); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abiomed, Medtronic, Pulnovo, Infraredx, Amgen, and Boehringer Ingelheim (personal payments); and stock or stock options for Cardiac Success, Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Valfix, and Xenter (personal ownership). SW reports research, travel, or educational grants to their institution from Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Bbraun, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Cleerly, Cordis Medical, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Farapulse, Fumedica, GE Medical Systems, Gebro Pharma, Guerbet, Idorsia, Inari Medical, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medalliance, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Neucomed, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pharming Tech, Pfizer, Philips AG, Polares, Regeneron, Sanofi-Aventis, Servier, Siemens Healthcare, Sinomed, SMT Sahajanand Medical Technologies, Terumo, Vifor, V-Wave, and Zoll Medical; payment to their institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Medtronic, Edwards, and Abbott; serving as an advisory board member or member of the steering or executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, and V-Wave with payments to the institution but no personal payments; is a member of the steering or executive committee group of several investigator-initiated trials that receive funding by industry without an effect on his personal remuneration; is an unpaid member of the Pfizer Research Award selection committee in Switzerland; is an expert panel member of the Clinical Study Group of the Deutsches Zentrum für Herz Kreislauf-Forschung and the Global Cardiovascular Research Funder Forum; and is the ESC Vice-President and Editor of the PCR EAPCI Textbook on Cardiovascular Medicine. MCG reports support for the present manuscript (eg, funding, provision of study materials, medical writing, and article processing charges) from Amgen (payment to Baim Institute), CSL Behring (payment to Beth Israel Deaconess Medical Center), Janssen Pharmaceuticals (payment to Beth Israel Deaconess Medical Center), and Johnson & Johnson Corporation (payment to Beth Israel Deaconess Medical Center); consulting fees from Amgen, Angel/Avertix Medical, AstraZenca, Bayer Corporation, Beren Therapeutics, Bioclinica, Boehringer Ingelheim, Boston Clinical Research Institute, Boston Scientific, Bristol-Myers Squibb, Cardenal Therapeutics, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, Duke Clinical Research Institute, Esperion, EXCITE International (US$0 received), Faraday Pharmaceuticals, Fortress Biotech, Gilead Sciences, HeartFlow, Inari, Intellia Therapeutics, Janssen Pharmaceuticals, Johnson & Johnson Corporation, Lumanity, MashUp MD, MD Magazine, Merck, MjHealth, NovoNordisk, PERT Consortium, Pfizer, PhaseBio, Revance Therapeutics, Samsung, SCAI, SFJ, Solstic Health/New Amsterdam Pharma, Somahlution/Marizyme, Synergia Medical, Vectura, Web MD, and Woman As One; is the Chief Executive Officer of the Baim Institute; and has stock or stock options for Absolutys, Dyad Medical, Flow Therapy, Fortress Biotech, Generable, HeartBeam, and nference. PV reports consulting fees from the Janssen BMS Alliance, Daiichi Sankyo, and CLS Behring. SM reports grants or contracts from Abbott Vascular, Amgen, BMS, and Janssen; and consulting fees from Novartis and Novo Nordisk. RDL reports grants or contracts from Amgen, Medtronic, Bristol-Myers Squibb, Pfizer, Glaxo Smith Kline, and Sanofi; consulting fees from AstraZeneca, Novo Nordisk, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Daiichi Sankyo, and Novo Nordisk. GDD reports grants from Daiichi-Sankyo. EPM reports consulting fees from Biosensors Europe, Cardialysis, and the Department of Clinical Research, University of Bern; support for attending meetings or travel from Abbott Vascular, Menarini, and Shockwave; and participation on a data safety monitoring board or advisory board for Abbott Vascular and Coreaalst. DJA reports grants from Amgen, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Sanofi, CSL Behring, Eisai, Gilead, Idorsia Pharmaceuticals, Matsutani Chemical Industry, Novartis, Osprey Medical, Renal Guard Solutions, Scott R MacKenzie Foundation, and Astra Zeneca; and personal fees from Amgen, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, CSL Behring, Novartis, Astra Zeneca, Abbott, Vectura, Novo Nordisk, and Faraday. SL reports consulting fees from ICON, Novo Nordisk, BMS/Pfizer, and AstraZeneca; and support for attending meetings or travel from the European Society of Cardiology. DH is employed by the Department of Clinical Research, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, the Department of Clinical Research is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organisations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of conflicts of interest see https://www.ctu.unibe.ch/research_projects/declaration_of_interest/index_eng.html. RM reports grants or contracts from Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi, and Zoll (institutional research); consulting fees from Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Daiichi Sankyo, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe NV, and Radcliffe (personal fees); honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the American College of Cardiology Board of trustees, StC Member, and AMA (JAMA Associate Editor); leadership or a fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, from the American Medical Association (Scientific Advisory Board, JAMA Cardiology Associate Editor), American College of Cardiology (Board of Trustees Member and Steering Committee Member of the Clinical Trial Research Program), and the Society for Cardiovascular Angiography & Interventions (Women in Innovations committee member); stock or stock options for Elixir Medical, Stel, and ControlRad; and was a faculty member but recieves no fees from the Cardiovascular Research Foundation. M-KH reports institutional research grants from Sam Jin Pharmaceuticals and Chong Kun Dang Pharmaceuticals; and honoraria for lectures from Medtronics and Edward Lifesciences. All other authors declare no competing interests.
Comment in
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Is this the conclusive evidence for ticagrelor monotherapy in acute coronary syndromes?Lancet. 2024 Sep 7;404(10456):908-909. doi: 10.1016/S0140-6736(24)01678-7. Epub 2024 Aug 31. Lancet. 2024. PMID: 39226908 No abstract available.
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