Association of Bleeding Severity with Mortality with Extended Thromboprophylaxis in the Medically Ill in the Mariner Trial
Bibliographic record
Abstract
Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MARINER study (NCT02111564) compared thromboprophylaxis with rivaroxaban (10mg daily or 7.5mg daily in subjects with creatinine clearance 30-<50ml/min at baseline) vs placebo for 45 days beyond hospital discharge to prevent symptomatic VTE in acutely ill medical patients while reducing bleeding events through patient selection (Spyropoulos AC et al NEJM 2018). Rivaroxaban did not significantly lower the composite of symptomatic VTE and VTE-related death but reduced symptomatic VTE (0.18% vs 0.42%, p=0.023). While major bleeding (MB) was infrequent in both study groups (0.28% vs 0.15% with rivaroxaban vs. placebo, p=0.124), there was more non-major clinically relevant bleeding (NMCRB) with rivaroxaban (1.42% vs 0.85%, HR 1.66, 95%CI 1.17-2.35, p=0.004). Although MB has been associated with increased mortality, the relationship between NMCRB and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MARINER trial with MB but not those with NMCRB would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 75 visit in 3 mutually exclusive groups: (1) subjects with no MB or NMCRB; (2) subjects whose first event was NMCRB; and (3) subjects whose first event was MB. Subjects only developing minimal or trivial bleeding were grouped with those who had no bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates that were significantly associated with ACM at p<0.05 (age, sex, history of VTE, history of anemia), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM among subjects who had a NMCRB was not increased over that in subjects without bleeding (2/136, 1.5% vs 218/11800, 1.8%, HR 0.41 95%CI 0.10, 1.67, p=0.213), while those experiencing MB had a higher incidence of death (4/26, 15.4% vs 218/11800, 1.8%, HR 3.43 95%CI 1.23, 9.54, p=0.018). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and the MARINER trial excluded subjects at a high risk of bleeding. Conclusion: Although few subjects had MB events, those who did had an increased risk of ACM, while those who had NMCRB events did not. This suggests that the modest increase in NMCRB in trials of extended thromboprophylaxis may be an acceptable tradeoff to prevent VTE. Disclosures Spyropoulos: Janssen R&D, LLC: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Bayer Healthcare: Consultancy; Portola: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Ageno:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Albers:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy. Elliott:Bayer Healthcare: Consultancy; University of Cincinnati: Honoraria; Spectrum Health: Honoraria; Janssen R&D, LLC: Consultancy. Halperin:Ortho-McNeil-Janssen: Consultancy; Johnson & Johnson: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; NIH: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Hiatt:Bayer Healthcare: Consultancy; NIH: Research Funding; Janssen R&D, LLD: Consultancy. Maynard:Janssen R&D, LLC: Consultancy. Steg:Novartis: Consultancy; Regeneron: Consultancy; Lilly: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amarin: Consultancy; Servier: Consultancy, Research Funding; Merck: Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Research Funding; Janssen R&D, LLC: Consultancy, Research Funding; AstraZeneca: Consultancy. Weitz:Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Honoraria; Janssen R&D, LLC: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Sugarmann:Janssen Research and Development LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Raskob:Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Pfizer: Consultancy, Honoraria; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; BMS: Consultancy, Honoraria; Janssen R&D, LLC: Consultancy, Honoraria; Portola: Consultancy; Novartis: Consultancy; Bayer Healthcare: Consultancy, Honoraria. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. The study evaluated the efficacy and safety of rivaroxaban post-hospitalization in subjects with an acute medical illness as thromboprophylaxis for venous thromboembolism.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".