Is There Really a Benefit to Net Clinical Benefit in Testing Antithrombotics?
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 14 Linguagem: Inglês
10.1161/circulationaha.117.033442
ISSN1524-4539
AutoresPhilippe Gabríel Steg, Deepak L. Bhatt,
Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoHomeCirculationVol. 137, No. 14Is There Really a Benefit to Net Clinical Benefit in Testing Antithrombotics? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessArticle CommentaryPDF/EPUBIs There Really a Benefit to Net Clinical Benefit in Testing Antithrombotics? Philippe Gabriel Steg, MD and Deepak L. Bhatt, MD, MPH Philippe Gabriel StegPhilippe Gabriel Steg FACT, French Alliance for Cardiovascular Trials; Hôpital Bichat, AP-HP; Université Paris-Diderot; and INSERM U-1148, France (P.G.S.) Royal Brompton Hospital, Imperial College, London, United Kingdom (P.G.S.) and Deepak L. BhattDeepak L. Bhatt Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA (D.L.B.) Originally published3 Apr 2018https://doi.org/10.1161/CIRCULATIONAHA.117.033442Circulation. 2018;137:1429–1431The evaluation of novel antithrombotics requires a careful assessment of both efficacy and safety. Assessment of efficacy typically relies on a composite of cardiovascular death, myocardial infarction, and stroke (major adverse cardiac events) that are supposedly hard clinical outcomes with objective definitions that can be adjudicated in blinded fashion. There are well-known problems related to using composite outcome measures1 such as the effect of a new treatment on components of the composite being different in magnitude or in direction, or the fact that these components have markedly different severity, leading some to propose the weighting of different events based on their associated rates of disability or subsequent attributable mortality. In recent years, for instance, there has been increasing concern that some myocardial infarctions are actually rather clinically minor events in which minute amounts of myocardial injury can be detected by ultrasensitive high-sensitivity troponin. Assessment of safety generally relies on measuring rates of bleeding, categorized according to one or several of the many existing bleeding event classifications, although some antithrombotic agents can have off-target effects (such as dyspnea in the case of ticagrelor).The desire to assess the balance of risk and benefit in a single quantitative measure, and the wish to create a composite outcome encompassing both efficacy and safety, as well, have led to the computation of new composite variables: net clinical benefit (ie, the difference between the number of major adverse cardiac events avoided and the price to pay in terms of excess bleeding events) or net adverse clinical events (the combination of major adverse cardiac events and bleeding events). These composite end points are also often used because, by combining more outcome events than conventional composites, they allow accrual of a greater number of outcome events and therefore raise the hope of lowering the sample size required for clinical trials. Ironically, the latter is often not true, because what has the greatest impact on power is not the crude number of outcome events, but the magnitude of the expected relative risk reduction achieved by treatment. By combining efficacy and safety into a single measure, because many agents have opposite effects on these outcomes, the resulting expected relative risk reduction is generally lower than the separate impact of any given agent on either efficacy or safety, and the resulting sample size requirement is larger. In addition, these composite outcomes carry a number of substantial limitations.First, there is an ongoing debate about how to best categorize bleeding events and which events are clinically important. Bleeding (even major bleeding) is rarely fatal or irreversible (with the exception of intracranial hemorrhage, spinal bleeding, some intraocular bleeding). But although these extremely severe events are relatively rare, restricting assessment of bleeding to these events is likely to overestimate the safety of novel agents. Although bleeding classifications often use somewhat subjective terms such as major, minor, severe, and life-threatening (even if these events are categorized and blindly adjudicated as objectively as possible), it is clear that some events that are described as being of minor importance can actually have disastrous consequences. For example, so-called nuisance bleeds have been shown to increase the risk of discontinuation of antiplatelet therapy after stenting, with catastrophic consequences.Second, when balancing ischemic benefit and bleeding risk, it is desirable to use events of similar severity in both terms of the equation. Cardiovascular death, stroke, and myocardial infarction are definitive events with irreversible harm (loss of life, neurons, or myocardium) and often permanent residual disability or organ dysfunction. Conversely, even severe bleeding may be a purely transient phenomenon and may leave no residual disability. Indeed, the subsequent mortality risk from major bleeding events is sometimes restricted to the first few weeks or months,2,3 whereas the risk of death following myocardial infarction is sustained.4 To provide a better assessment of the severity of myocardial infarction types, the universal definition of myocardial infarction5 recommends providing a detailed tabulation of the various types of myocardial infarction, according to multiples of the 99th percentile upper reference limit of the applied cardiac biomarker (typically troponin).Third, most, if not all novel antithrombotics will result in improved efficacy at the expense of increased bleeding and therefore will tend to skew net clinical benefit toward a null value. Assuming the extreme example of zero net clinical benefit, it becomes impossible to know whether the latter is a reflection of improved efficacy at the expense of equivalent increased bleeding, improved safety at the expense of reduced efficacy, or the mere result of a totally inactive agent (which would have no efficacy or safety) (Figure).Download figureDownload PowerPointFigure. Bivariate assessment of efficacy and safety of a novel antithrombotic. Most novel agents would be expected to fall in the lower right quadrant, reflecting improved efficacy at the expense of an increased risk of bleeding. The diagonal line represents the line for zero net clinical benefit (NCB). An ideal agent would achieve greater efficacy and greater safety than the existing control. The 3 theoretical agents A, B, and C all achieve the same null NCB, but A is more effective than control but at the expense of increased bleeding, B is less effective but achieves greater safety, and C has no effect on efficacy or safety.Fundamentally, the assessment of the efficacy and safety of antithrombotics is a bivariate exercise5 and summarizing it in a unidimensional variable can be misleading. It is preferable to describe simply and objectively, without committing to value judgment, the entire spectrum of ischemic and bleeding outcomes, preferably using more than one among the widely accepted and detailed classifications of bleeding events and providing a detailed categorization of nonfatal ischemic events, in particular, myocardial infarction. This helps physicians and patients reach a truly informed decision on whether benefits likely exceed risks for each individual patient.Sources of FundingThis work was supported in part by the RHU iVASC grant ANR-16-RHUS-00010 from the French National Research Agency (ANR) as part of the Investissements d'Avenir program.DisclosuresDr Steg discloses the following relationships: Research grant from Bayer, Merck, Sanofi, and Servier. Speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer-Ingelheim, Bristol-Myers-Squibb, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier.Dr Bhatt discloses the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), 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), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott); Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circ.ahajournals.orgPhilippe Gabriel Steg, MD, INSERM U1148, Département de Cardiologie, Hôpital Bichat, 46 Rue Henri Huchard, 75018 Paris, France. E-mail [email protected]References1. Pocock SJ, McMurray JJV, Collier TJ. Statistical controversies in reporting of clinical trials: part 2 of a 4-part series on statistics for clinical trials.J Am Coll Cardiol. 2015; 66:2648–2662. doi: 10.1016/j.jacc.2015.10.023.CrossrefMedlineGoogle Scholar2. Ducrocq G, Schulte PJ, Becker RC, Cannon CP, Harrington RA, Held C, Himmelmann A, Lassila R, Storey RF, Sorbets E, Wallentin L, Steg PG. Association of spontaneous and procedure-related bleeds with short- and long-term mortality after acute coronary syndromes: an analysis from the PLATO trial.EuroIntervention. 2015; 11:737–745. doi: 10.4244/EIJY14M09_11.CrossrefMedlineGoogle Scholar3. Secemsky EA, Yeh RW, Kereiakes DJ, Cutlip DE, Cohen DJ, Steg PG, Cannon CP, Apruzzese PK, D'Agostino RB, Massaro JM, Mauri L; Dual Antiplatelet Therapy (DAPT) Study Investigators. Mortality following cardiovascular and bleeding events occurring beyond 1 year after coronary stenting: a secondary analysis of the Dual Antiplatelet Therapy (DAPT) study.JAMA Cardiol. 2017; 2:478–487. doi: 10.1001/jamacardio.2017.0063.CrossrefMedlineGoogle Scholar4. Kittelson JM, Spyropoulos AC, Halperin JL, Kessler CM, Schulman S, Steg G, Turpie AG, Cutler NR, Hiatt WR, Goldenberg NA; Antithrombotic Trials Leadership and Steering (ATLAS) Group. Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach.J Thromb Haemost. 2013; 11:1443–1448. doi: 10.1111/jth.12324.CrossrefMedlineGoogle Scholar5. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasché P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction.Circulation. 2012; 126:2020–2035. doi: 10.1161/CIR.0b013e31826e1058.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Matsui K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A and Ogawa H (2022) The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial, BMC Medicine, 10.1186/s12916-022-02268-6, 20:1, Online publication date: 1-Dec-2022. Ducrocq G, Bhatt D, Lee J, Kui N, Fox K, Harrington R, Leiter L, Mehta S, Kiss R, James S, Vinereanu D, Huber K, Andersson M, Himmelmann A, Simon T and Steg P (2022) Balance of benefit and risk of ticagrelor in patients with diabetes and stable coronary artery disease according to bleeding risk assessment with the CRUSADE score: Data from THEMIS and THEMIS PCI, American Heart Journal, 10.1016/j.ahj.2022.03.008, 249, (23-33), Online publication date: 1-Jul-2022. Goto S, McGuire D and Goto S (2022) The Future Role of High-Performance Computing in Cardiovascular Medicine and Science -Impact of Multi-Dimensional Data Analysis-, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.RV17062, 29:5, (559-562), Online publication date: 1-May-2022. Kwon O and Park D (2022) Antithrombotic Therapy After Acute Coronary Syndromes or Percutaneous Coronary Interventions in East Asian Populations, JACC: Asia, 10.1016/j.jacasi.2021.12.005, 2:1, (1-18), Online publication date: 1-Feb-2022. Bershtein L, Zbyshevskaya E and Gumerova V (2021) Optimum Treatment Strategy in Chronic Coronary Syndromes: the New Trials vs the Current Guidelines, Rational Pharmacotherapy in Cardiology, 10.20996/1819-6446-2021-10-02, 17:5, (761-770) Maksimova M, Fonyakin A and Geraskina L (2021) Prevention of ischemic stroke in atrial fibrillation from the point of view of a neurologist. Standards and real clinical practice, Terapevticheskii arkhiv, 10.26442/00403660.2021.10.201105, 93:10, (1240-1245) Hardung D, Behne A, Boral M, Giesche C and Langhoff R (2021) Antithrombotic Treatment for Peripheral Arterial Occlusive Disease, Deutsches Ärzteblatt international, 10.3238/arztebl.m2021.0157 Patel P, Henderson R, Bolliger D, Erdoes G and Mazzeffi M (2021) The Year in Coagulation: Selected Highlights from 2020, Journal of Cardiothoracic and Vascular Anesthesia, 10.1053/j.jvca.2021.02.057, 35:8, (2260-2272), Online publication date: 1-Aug-2021. Eikelboom J, Bhatt D, Fox K, Bosch J, Connolly S, Anand S, Avezum A, Berkowitz S, Branch K, Dagenais G, Félix C, Guzik T, Hart R, Maggioni A, Muehlhofer E, Sharma M, Shestakovska O and Yusuf S (2021) Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease, Journal of the American College of Cardiology, 10.1016/j.jacc.2021.04.083, 78:1, (14-23), Online publication date: 1-Jul-2021. Ko E and Park D (2021) Optimal Antithrombotic Strategy After Transcatheter Aortic Valve Replacement: Is the "Less Is More" Concept Always Better?, Journal of the American Heart Association, 10:9, Online publication date: 4-May-2021. van der Sangen N, Rozemeijer R, Chan Pin Yin D, Valgimigli M, Windecker S, James S, Buccheri S, ten Berg J, Henriques J, Voskuil M and Kikkert W (2021) Patient-tailored antithrombotic therapy following percutaneous coronary intervention, European Heart Journal, 10.1093/eurheartj/ehaa1097, 42:10, (1038-1046), Online publication date: 7-Mar-2021. Steffel J, Ruff C, Yin O, Braunwald E, Park J, Murphy S, Connolly S, Antman E and Giugliano R (2021) Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation, Journal of the American College of Cardiology, 10.1016/j.jacc.2020.12.053, 77:9, (1197-1207), Online publication date: 1-Mar-2021. Bates E (2020) Net Adverse Clinical Events With Antiplatelet Therapy in Acute Coronary Syndromes, JAMA, 10.1001/jama.2020.16238, 324:16, (1613), Online publication date: 27-Oct-2020. Khan S, Singh M, Valavoor S, Khan M, Lone A, Khan M, Khan M, Mani P, Kapadia S, Michos E, Stone G, Kalra A and Bhatt D (2020) Dual Antiplatelet Therapy After Percutaneous Coronary Intervention and Drug-Eluting Stents, Circulation, 142:15, (1425-1436), Online publication date: 13-Oct-2020. Capodanno D, Morice M, Angiolillo D, Bhatt D, Byrne R, Colleran R, Cuisset T, Cutlip D, Eerdmans P, Eikelboom J, Farb A, Gibson C, Gregson J, Haude M, James S, Kim H, Kimura T, Konishi A, Leon M, Magee P, Mitsutake Y, Mylotte D, Pocock S, Rao S, Spitzer E, Stockbridge N, Valgimigli M, Varenne O, Windhovel U, Krucoff M, Urban P and Mehran R (2020) Trial Design Principles for Patients at High Bleeding Risk Undergoing PCI, Journal of the American College of Cardiology, 10.1016/j.jacc.2020.06.085, 76:12, (1468-1483), Online publication date: 1-Sep-2020. Calderone D, Capodanno D and Angiolillo D (2020) An updated drug profile of ticagrelor with considerations on the treatment of patients with coronary artery disease and diabetes mellitus, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2020.1792293, 18:8, (449-464), Online publication date: 2-Aug-2020. Hara H, van Klaveren D, Takahashi K, Kogame N, Chichareon P, Modolo R, Tomaniak M, Ono M, Kawashima H, Wang R, Gao C, Niethammer M, Fontos G, Angioi M, Ribeiro V, Barbato E, Leandro S, Hamm C, Valgimigli M, Windecker S, Jüni P, Steg P, Verbeeck J, Tijssen J, Sharif F, Onuma Y and Serruys P (2020) Comparative Methodological Assessment of the Randomized GLOBAL LEADERS Trial Using Total Ischemic and Bleeding Events, Circulation: Cardiovascular Quality and Outcomes, 13:8, Online publication date: 1-Aug-2020. Bhatt D and Steg P (2020) Differential effect of ticagrelor on irreversible harms in diabetes – Authors' reply, The Lancet, 10.1016/S0140-6736(20)30479-7, 396:10244, (93-94), Online publication date: 1-Jul-2020. Bhatt D, Eikelboom J, Connolly S, Steg P, Anand S, Verma S, Branch K, Probstfield J, Bosch J, Shestakovska O, Szarek M, Maggioni A, Widimský P, Avezum A, Diaz R, Lewis B, Berkowitz S, Fox K, Ryden L, Yusuf S, Aboyans V, Alings M, Commerford P, Cook-Bruns N, Dagenais G, Dans A, Ertl G, Felix C, Guzik T, Hart R, Hori M, Kakkar A, Keltai K, Keltai M, Kim J, Lamy A, Lanas F, Liang Y, Liu L, Lonn E, Lopez-Jaramillo P, Metsarinne K, Moayyedi P, O'Donnell M, Parkhomenko A, Piegas L, Pogosova N, Sharma M, Stoerk S, Tonkin A, Torp-Pedersen C, Varigos J, Verhamme P, Vinereanu D, Yusoff K and Zhu J (2020) Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease, Circulation, 141:23, (1841-1854), Online publication date: 9-Jun-2020. Steg P, Ducrocq G, Bhatt D, Hohnloser S, Nordaby M, Miede C, Lip G, Oldgren J, ten Berg J and Cannon C (2020) Dabigatran Dual Therapy Versus Warfarin Triple Therapy Post PCI in Patients With Atrial Fibrillation, Journal of the American College of Cardiology, 10.1016/j.jacc.2019.11.012, 75:2, (238-240), Online publication date: 1-Jan-2020. Nelson A and Alexander J (2019) Anticoagulation-Related Major Bleeding in Patients With Atrial Fibrillation, Circulation, 140:22, (1802-1804), Online publication date: 26-Nov-2019. Steg P, Bhatt D, Simon T, Fox K, Mehta S, Harrington R, Held C, Andersson M, Himmelmann A, Ridderstråle W, Leonsson-Zachrisson M, Liu Y, Opolski G, Zateyshchikov D, Ge J, Nicolau J, Corbalán R, Cornel J, Widimský P and Leiter L (2019) Ticagrelor in Patients with Stable Coronary Disease and Diabetes, New England Journal of Medicine, 10.1056/NEJMoa1908077, 381:14, (1309-1320), Online publication date: 3-Oct-2019. Fanaroff A, Cyr D, Neely M, Bakal J, White H, Fox K, Armstrong P, Lopes R, Ohman E and Roe M (2018) Days Alive and Out of Hospital: Exploring a Patient-Centered, Pragmatic Outcome in a Clinical Trial of Patients With Acute Coronary Syndromes, Circulation: Cardiovascular Quality and Outcomes, 11:12, Online publication date: 1-Dec-2018. April 3, 2018Vol 137, Issue 14 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.033442PMID: 29610124 Originally publishedApril 3, 2018 Keywordstreatment outcomefibrinolytic agentsriskhemorrhagesafetymyocardial infarctionPDF download Advertisement SubjectsCoronary Artery DiseaseThrombosis
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