Title: Definition of clinically relevant non‐major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non‐surgical patients: communication from the SSC of the ISTH
Abstract: Journal of Thrombosis and HaemostasisVolume 13, Issue 11 p. 2119-2126 Recommendations and GuidelinesFree Access Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH S. Kaatz, Corresponding Author S. Kaatz Department of Medicine, Hurley Medical Center, Flint, MI, USA Correspondence: Scott Kaatz, Hurley Medical Center, One Hurley Plaza, Clinical Associate Professor of Medicine, Michigan State University College of Human Medicine, Flint, MI 48503, USA. Tel.: +1 810 262 6281; fax: +1 810 262 9003. E-mail: [email protected] for more papers by this authorD. Ahmad, D. Ahmad Division of Hematology and Oncology, Department of Medicine, Michigan State University, East Lansing, MI, USASearch for more papers by this authorA. C. Spyropoulos, A. C. Spyropoulos Anticoagulation and Clinical Thrombosis Services, North Shore-LIJ Health System, Manhasset, NY, USA Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USASearch for more papers by this authorS. Schulman, S. Schulman Department of Medicine, Thrombosis Service, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, CanadaSearch for more papers by this author for the Subcommittee on Control of Anticoagulation, the Subcommittee on Control of AnticoagulationSearch for more papers by this author S. Kaatz, Corresponding Author S. Kaatz Department of Medicine, Hurley Medical Center, Flint, MI, USA Correspondence: Scott Kaatz, Hurley Medical Center, One Hurley Plaza, Clinical Associate Professor of Medicine, Michigan State University College of Human Medicine, Flint, MI 48503, USA. Tel.: +1 810 262 6281; fax: +1 810 262 9003. E-mail: [email protected] for more papers by this authorD. Ahmad, D. Ahmad Division of Hematology and Oncology, Department of Medicine, Michigan State University, East Lansing, MI, USASearch for more papers by this authorA. C. Spyropoulos, A. C. Spyropoulos Anticoagulation and Clinical Thrombosis Services, North Shore-LIJ Health System, Manhasset, NY, USA Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USASearch for more papers by this authorS. Schulman, S. Schulman Department of Medicine, Thrombosis Service, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, CanadaSearch for more papers by this author for the Subcommittee on Control of Anticoagulation, the Subcommittee on Control of AnticoagulationSearch for more papers by this author First published: 11 September 2015 https://doi.org/10.1111/jth.13140Citations: 575 Manuscript handled by: W. Ageno Final decision: F. R. Rosendaal, 30 August 2015 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Introduction The term ‘clinically relevant non-major bleeding’ (CRNMB) has recently been incorporated into the outcomes of atrial fibrillation (AF) and venous thromboembolic (VTE) disease clinical trials to further define a bleeding event that is neither a major bleed as defined by the International Society on Thrombosis and Haemostasis (ISTH) 1 nor a non–clinically consequential minor bleeding event. This relatively new term for anticoagulant-related bleeding suffers the same lack of harmonization as major bleeding did a decade ago. Responding to the wide range of definitions of major bleeding in clinical trials, several groups have released recommendations to standardize the definition of ‘major bleeding.’ The subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee (SSC) established a standard definition of major bleeding in non-surgical patients 1. The European Medicines Agency draft guideline on clinical investigation of medicinal products for the prevention of stroke and systemic embolic events in patients with non-valvular AF is closely aligned with this definition 2. In an attempt to standardize the definition of bleeding in acute coronary syndromes, the Bleeding Academic Research Consortium convened a meeting with representatives from academic research organizations, the U.S. Food and Drug Administration (FDA), the National Institutes of Health, pharmaceutical and cardiovascular device manufacturers, and independent physician thought leaders to standardize bleeding definitions 3. Although much work has been done to harmonize the definition of major bleeding, there have been no attempts for CRNMB. The purpose of this ISTH SSC recommendation is to provide a standard definition of CRNMB that can be used in clinical trials, registries, and cohort studies of AF and VTE and can be applied uniformly in pooled systematic reviews and by regulatory authorities. The authors worked with the chair of the SSC Subcommittee on Control of Anticoagulation and presented the planned literature search, study inclusion criteria and data abstraction strategy at the 60th SSC meeting in 2014 for comments and feedback, which were incorporated into recommendations. Conflicting author opinions were resolved by consensus and the original draft manuscript was approved by the SSC co-chairs. Methods We limited our literature review to trials in patients with AF and VTE because the work of the Bleeding Academic Research Consortium has already addressed this issue in other cardiovascular trials 3. We limited our review to clinical trials, as this definition is most likely to be used in meta-analytic studies and guidelines and by regulatory authorities. We performed MEDLINE searches, but “clinically relevant non-major bleeding” and “clinical relevant non major bleeding” (without hyphen) are not medical search headings (MeSH) and this strategy resulted in disparate results of 65 and 188 retrieved articles, respectively. Multiple search attempts using MeSH headings for VTE, AF, bleeding, prophylaxis, etc. continued to have low sensitivity to known clinical trials that have reported CRNMB as an outcome. The term ‘CRNMB’ has recently been incorporated into FDA's prescribing information on some of the newer, novel, non–vitamin K, target-specific, direct oral anticoagulants (DOACs). This term is not mentioned as an adverse reaction for warfarin (Coumadin), enoxaparin, tinzaparin, dalteparin, or fondaparinux and is not listed for any of the indications approved prior to 2012 for dabigatran, rivaroxaban, or apixaban by the FDA. We used these findings as a guide and limited our literature review to phase III clinical trials in AF, VTE prophylaxis in medical patients, and VTE treatment that would likely to be used for drug approval in multiple countries. Definitions of CRNMB were extracted from the clinical trial reports and, when available, from the protocols if included as a supplement. Findings We reviewed 17 phase III trials of DOACs that used CRNMB as an outcome. We found little consistency in the definition used between trials overall, or within the condition or DOAC being studied.. We identified 47 different elements of bleeding used to define CRNMB including seven different definitions of nose bleeding (Table 1). Table 1. Criteria used to define clinically relevant non-major bleeding in phase III clinical trials of venous thromboembolism and atrial fibrillation with direct oral anticoagulants Category of phase III trials DOAC in medical VTE prophylaxis DOAC in atrial fibrillation DOAC in VTE treatment Study name, reference ADOPT, Goldhaber 6 MAGELLAN, Cohen 7 RELY, Connolly 8 ROCKET-AF, Patel 9 ROCKET- J, Hori 10 ARISTOTLE, Granger 11 AVERROES, Connolly 12 ARISTOTLE J A.Fib, Ogawa 13 ENGAGE, Giugliano 14 EINSTEIN-DVT, Bauersachs 15 EINSTEIN-PE, Büller 16 RECOVER, Schulman 17 RECOVER II, Schulman 18 REMEDY AND RESONATE, Schulman 19 AMPLIFY-EXT, Agnelli 20 AMPLIFY, Agnelli 21 Hokusai-VTE, Buller 22 Not meeting the criteria for major bleeding × × × × × × × × × × × × Medical intervention × × × × × × × × × × × × Unscheduled contact with a physician (visit or call) × × × × × × × × Temporary cessation of study treatment × × × × × × × × × Discomfort for the subject such as pain × × × × × × × × Impairment of activities of daily life × × × × × × × × Any bleeding compromising hemodynamics × × × Any bleeding needed surgical intervention × × × × × × × Change in antithrombotic therapy × × × × Requires a change in concomitant therapy × Leading to hospitalization × × × × × × × × × × Requires/prolongs hospitalization × Multiple source bleeding × Bleeding leading to a transfusion of < 2 units of whole blood or red cells × × × Spontaneous skin hematoma > 25 cm2 × × × Provoked subcutaneous hematoma > 25 cm2 × > 100-cm2 intramuscular hematoma × Intramuscular hematoma documented by ultrasonography × Radiographically confirmed hematoma × Intramuscular hematoma × × Subcutanous skin hematoma > 25 or 100 cm2 if provoked × × × Epistaxis lasting > 5 min × × × × × Epistaxis lasting > 5 min in the absence of external factors × × × Repetitive epistaxis × Repetitive epistaxis (two or more episodes of bleeding more extensive than spots on a handkerchief within 24 h) × × × Epistaxis requiring medical attention × Epistaxis leading to an intervention × × × × Requires nasal packing or compression × Gingival bleeding occurring spontaneously × × × Gingival bleeding lasting > 5 min × × × × × × Macroscopic hematuria spontaneous × × × × × × × × Macroscopic hematuria lasting > 24 h after instrumentation (catheter or surgery) × × × × × × × × Macroscopic gastrointestinal hemorrhage × × × × One episode of melena × × × × One episode of hematemesis × × × × If clinically apparent and positive occult blood × × × × Rectal blood loss × × × × × × × More than few spots on toilet paper × × × × × × × Gastrointestinal bleeding containing frank blood or coffee-ground material that tested positive for blood, endoscopically confirmed bleeding × Hemoptysis more than few speckles and not occurring in pulmonary embolism context × × × Hemoptysis × × Any other bleeding event judged as clinically significant by the investigator × × × × × Required laboratory evaluation × Requires imaging study × Requires a therapeutic procedure × Recommendations The definition of CRNMB should align with the Bleeding Academic Research Consortium's (BARC) 3 recommendations to maintain harmony across VTE/AF and other cardiovascular trials. BARC bleeding definitions do not use the terms ‘major bleeding’ or ‘CRNMB’ and are classified as types 0 (no bleeding), 1 (bleeding that is not actionable), 2 (overt actionable bleeding that is not type 3, 4, or 5), 3a (overt bleeding with hemoglobin drop of 3 to ≤ 5 g dL−1), 3b (overt bleeding with hemoglobin drop ≥ 5 g dL−1), 3c (intracranial hemmorage), 4 (coronary artery bypass grafting [CABG] related), 5a (probable fatal bleeding), and 5b (definite fatal bleeding).. BARC type 2 bleeding most closely aligns with our proposed definition of CRNMB and is defined as: ‘any overt, actionable sign of hemorrhage (eg, more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (i) requiring nonsurgical, medical intervention by a healthcare professional, (ii) leading to hospitalization or increased level of care, or (iii) prompting evaluation.’ Several modifications to this definition are required to also align with the ISTH definition of major bleeding and to account for BARC type 4 bleeding (CABG related) that is not typically applicable to AF and VTE studies. Overt bleeding is incorporated into many bleeding definitions to guard against hemodilution being counted as an event, and we proposed dropping this requirement. As an example, a slow decline in hemoglobin may not have overt bleeding (no melena) but could prompt endoscopic evaluation that could uncover a bleeding source and would be considered clinically relevant. We also recommend a hemoglobin drop of ≥ 2 g dL−1 (opposed to BARC 3a [3 to < 5 g dL−1]) be considered major bleeding to align with the ISTH definition. We therefore recommend the following criteria to be used for the definition of clinical relevant non-major bleeding in AF and non-surgical VTE studies: Any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: requiring medical intervention by a healthcare professional leading to hospitalization or increased level of care prompting a face to face (i.e., not just a telephone or electronic communication) evaluation ISTH major bleeding in non-surgical patients is defined as having a symptomatic presentation and 1: Fatal bleeding, and/or Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or Bleeding causing a fall in hemoglobin level of 20 g L−1 (1.24 mmol L−1) or more, or leading to transfusion of two or more units of whole blood or red cells. Discussion A simple, pragmatic definition of CRNMB is any bleeding that leads to a face-to-face evaluation, however, we chose to closely align the SSC definition of CRNMB with that of the BARC recommendations to help harmonize the definition across AF, VTE, and acute coronary syndrome studies. So-called ‘minor’ or ‘nuisance’ bleeding events are important as patient-centric outcomes, since they may influence the perception of decreased quality of life 4 and may not be ‘minor’ to the patient. As an example, a patient with increase menstrual flow after starting anticoagulation may have decrease quality of life; however, unless this prompts a face-to-face evaluation for a physical examination or laboratory testing, it would not be classified as CRNMB. Therefore, ‘minor’ bleeding may be required in the reporting of clinical trials by regulatory authorities, although they may be difficult to find and underreported in retrospective or large data studies and hence are not incorporated into the ISTH definition of CRNMB. Additionally, this definition also does not account for bleeding that leads to patients discontinuing anticoagulants without seeking medical attention, consistent with BARC recommendations. CRNMB is vital to report since it incurs time-consuming management and increased costs 5. CRNMB has become an important primary or secondary safety endpoint in clinical studies of AF and VTE. The proposed standardized and practical definition of CRNMB is meant to be applied in clinical trials of non-surgical patients with AF and VTE, but can also be incorporated in observational and registry studies. This standardization of CRNMB should decrease the heterogeneity in meta-analytic pooling of trial results; be more easily applied to large database studies because the definition relies on clinical visits or procedure codes; allows harmonization across registries; and counts bleeding that directly relates to medical resource use for cost-effectiveness studies. We propose a definition of CRNMB that should be applicable to clinical trials and epidemiologic studies and is pragmatically easy to apply. We recommend investigators and regulatory authorities adopt this standardized definition. Addendum Concept and design of the manuscript: S. Kaatz, D. Ahmad, A. C. Spyropoulos, and S. Schulman. Critical writing: S. Kaatz, D. Ahmad, A. C. Spyropoulos, and S. Schulman. Revisions and final approval: S. Kaatz, D. Ahmad, A. C. Spyropoulos, and S. Schulman. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. 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