Risk assessment tools for bleeding in patients with unprovoked venous thromboembolism: an analysis of the PLATO-VTE study.

BACKGROUND: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk. OBJECTIVES: This study aimed to evaluate the performance of 5 bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-Bleeding). METHODS: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per International Society on Thrombosis and Haemostasis criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a "high risk" and "non-high risk" of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios (HRs). RESULTS: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95% CI, 0.48-0.68) for ABC-Bleeding, 0.56 (95% CI, 0.46-0.66) for RIETE, 0.53 (95% CI, 0.43-0.64) for CHAP, 0.50 (95% CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95% CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-Bleeding, and in the non-high-risk groups, it varied from 7.7% with ABC-Bleeding to 9.6% with RIETE. HRs ranged from 0.93 (95% CI, 0.46-1.9) for VTE-BLEED to 1.67 (95% CI, 0.86-3.2) for ABC-Bleeding. Recalibration at 3-month follow-up did not alter the results. CONCLUSION: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE.

Evaluating the Shock Index, Revised Assessment of Bleeding and Transfusion (RABT), Assessment of Blood Consumption (ABC) and novel PTTrauma score to predict critical transfusion threshold (CAT) in penetrating thoracic trauma.

The shock index (SI) has been associated with predicting transfusion needs in trauma patients. However, its utility in penetrating thoracic trauma (PTTrauma) for predicting the Critical Administration Threshold (CAT) has not been well-studied. This study aimed to evaluate the prognostic value of SI in predicting CAT in PTTrauma patients and compare its performance with the Assessment of Blood Consumption (ABC) and Revised Assessment of Bleeding and Transfusion (RABT) scores. We conducted a prognostic type 2, single-center retrospective observational cohort study on patients with PTTrauma and an Injury Severity Score (ISS) > 9. The primary exposure was SI at admission, and the primary outcome was CAT. Logistic regression and decision curve analysis were used to assess the predictive performance of SI and the PTTrauma score, a novel model incorporating clinical variables. Of the 620 participants, 53 (8.5%) had more than one CAT. An SI > 0.9 was associated with CAT (adjusted OR 4.89, 95% CI 1.64-14.60). The PTTrauma score outperformed SI, ABC, and RABT scores in predicting CAT (AUC 0.867, 95% CI 0.826-0.908). SI is a valuable predictor of CAT in PTTrauma patients. The novel PTTrauma score demonstrates superior performance compared to existing scores, highlighting the importance of developing targeted predictive models for specific injury patterns. These findings can guide clinical decision-making and resource allocation in the management of PTTrauma.

Bleeding assessment following central venous catheter placement, a direct comparison of prospective and retrospective analyses.

BACKGROUND: Reported bleeding incidences following central venous catheter (CVC) placement highly depend on methods of bleeding assessment. To determine the direction and magnitude of the bias associated with retrospective data collection, we used data from the PACER randomized controlled trial and a previous retrospective cohort study. STUDY DESIGN AND METHODS: A patient-level comparison of CVC-related bleeding severity was made among (1) the prospectively collected clinical bleeding assessment of the PACER trial, (2) centralized assessment of CVC insertion site photographs, and (3) retrospective chart review. Interrater reliability for photographic bleeding assessment and retrospective chart review was assessed using Cohen's κ. The magnitude of underreporting of both methods compared to prospective clinical bleeding assessment at different cutoff points of clinically relevant bleeding was assessed using McNemar's test. RESULTS: Interrater reliability was acceptable for both methods (κ = 0.583 and κ = 0.481 for photographic assessment and retrospective chart review, respectively). Photographic bleeding assessment led to significant underreporting of bleeding complications at all cutoff points. Retrospective chart review led to significant underreporting of minor bleeding complications, with an odds ratio (95% CI) of 0.17 (0.044-0.51) for the cutoff point grade 1 (i.e., self-limiting or requiring at most 20 min of manual compression) or higher. There was no significant underreporting of major bleeding complications with retrospective chart review. DISCUSSION: Centralized photographic bleeding assessment and retrospective chart review lead to biased bleeding assessment compared to prospective clinical bleeding assessment.

Predictors of adherence to direct oral anticoagulants after cardiovascular or bleeding events in Medicare Advantage Plan enrollees with atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are recommended for patients with atrial fibrillation (AF) given their improved safety profile. Suboptimal adherence to DOACs remains a significant concern among individuals with AF. However, the extent of adherence to DOACs following a cardiovascular or bleeding event has not been fully evaluated. OBJECTIVE: To evaluate the pattern of adherence trajectories of DOACs after a cardiovascular or bleeding event and to investigate the sociodemographic and clinical predictors associated with each adherence trajectory by using claims-based data. METHODS: This retrospective study was conducted among patients with AF prescribed with DOACs (dabigatran/apixaban/rivaroxaban) between July 2016 and December 2017 and who were continuously enrolled in the Texas-based Medicare Advantage Plan. Patients who experienced a cardiovascular or bleeding event while using the DOACs were further included in the analysis. The sample was limited to patients who experienced a clinical event such as a cardiovascular or bleeding event while using the DOACs. The clinical events considered in this study were cardiovascular (stroke, congestive heart failure, myocardial infarction, systemic embolism) and bleeding events. To assess adherence patterns, each patient with a DOAC prescription was followed up for a year after experiencing a clinical event. The monthly adherence to DOACs after these events was evaluated using the proportion of days covered (PDC). A group-based trajectory model incorporated the monthly PDC to classify groups of patients based on their distinct patterns of adherence. Predictors associated with each trajectory were assessed using a multinomial logistic regression model, with the adherent trajectory serving as the reference group in the outcome variable. RESULTS: Among the 694 patients with AF who experienced clinical events after the initiation of DOACs, 3 distinct adherence trajectories were identified: intermediate nonadherent (30.50%), adherent (37.7%), and low adherent (31.8%); the mean PDC was 0.47 for the intermediate nonadherent trajectory, 0.93 for the adherent trajectory, and 0.01 for low adherent trajectory. The low-income subsidy was significantly associated with lower adherence trajectories (odds ratio [OR] = 4.81; 95% CI = 3.07-7.51) and with intermediate nonadherent trajectories (OR = 1.57; 95% CI = 1.06-2.34). Also, nonsteroidal anti-inflammatory drug use was significantly associated with lower adherence trajectories (OR = 5.10; 95% CI = 1.95-13.36) and intermediate nonadherent trajectories (OR = 3.17; 95% CI = 1.26-7.93). Other predictors significantly associated with both nonadherent trajectories are type of DOACs (OR = 0.53; 95% CI = 0.35-0.79), presence of coronary artery disease (OR = 1.89; 95% CI = 1.01-3.55), and having 2 or more clinical events (OR = 1.65; 95% CI = 1.09-2.50). CONCLUSIONS: Predictors identified provide valuable insights into the suboptimal adherence of DOACs among Medicare Advantage Plan enrollees with AF, which can guide the development of targeted interventions to enhance adherence in this high-risk patient population.

Assessment of a randomized controlled trial on the safety of pre-placing bronchial balloons in transbronchial lung cryobiopsy for diagnosing interstitial lung disease.

RATIONALE AND OBJECTIVES: Bleeding is a major complication of transbronchial lung cryobiopsy (TBLC), and pre-placing a bronchial balloon is one of the clinical practices used to prevent it, but with very weak evidence, which should be confirmed. This study aimed to conduct whether pre-placing a bronchial balloon in TBLC for diagnosing interstitial lung disease (ILD) is more safety. MATERIALS AND METHODS: In this prospective, single-center, randomized controlled trial, patients with suspected ILD were enrolled and randomly assigned to pre-placed balloon and none-pre-placed balloon groups. The primary outcome was incidence of moderate bleeding in each group. The secondary endpoints were the incidence of severe bleeding, pneumothorax, and other procedural complications. RESULTS: Exactly 250 patients were enrolled between August 2019 and March 2022, with 125 in each group. There were no significant differences in severe bleeding between the none-pre-placed balloon group and pre-placed balloon group (1.6% vs. 0.8%; adjusted p = 0.520), while more moderate bleeding occurred in the none-pre-placed balloon group (26.4% vs. 6.4%, adjusted p = 0.001), as well as more use of hemostatic drug (28.0% vs. 6.4%, adjusted p = 0.001). Three patients in the none-pre-placed balloon group used the bronchial balloon. More samples could be acquired in the pre-placed balloon group than in the none-pre-placed balloon group (3.8 ± 0.9 vs. 3.1 ± 0.9, p < 0.001). There were no significant differences in multidisciplinary discussion (MDD) between the two groups (89.6% vs. 91.2%, adjusted p = 0.182). CONCLUSION: A pre-placed bronchial balloon can reduce the incidence of moderate bleeding and increase the confidence of the bronchoscopists. However, it had no effect on increasing the diagnostic rate of MDD and reducing severe bleeding. REGISTRATION NUMBER: NCT04047667 ( www. CLINICALTRIALS: gov identifier).

Analysis of long-term clinical and cost impact of etranacogene dezaparvovec for the treatment of hemophilia B population in the United States.

INTRODUCTION: Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB). OBJECTIVE: To estimate long-term clinical impact and cost of EDZ in the United States (US). METHODS: A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction. RESULTS: Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8. CONCLUSION: Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

This analysis assessed the long-term clinical and financial impact of introducing EDZ in the United States of America for people with severe or moderately severe hemophilia B. A decision-analytic model was developed comparing a scenario with EDZ and one without EDZ over 20 years. Introducing EDZ would avert 11,292 bleeds and 64 joint procedures over 20 years and would achieve cumulative cost savings in year 8, with a total cumulative 20-year cost saving of $2.32 billion.

Self-Administration of Aspirin After Chest Pain for the Prevention of Premature Cardiovascular Mortality in the United States: A Population-Based Analysis.

BACKGROUND: Aspirin, an effective, low-cost pharmaceutical, can significantly reduce mortality if used promptly after acute myocardial infarction (AMI). However, many AMI survivors do not receive aspirin within a few hours of symptom onset. Our aim was to quantify the mortality benefit of self-administering aspirin at chest pain onset, considering the increased risk of bleeding and costs associated with widespread use. METHODS AND RESULTS: We developed a population simulation model to determine the impact of self-administering 325 mg aspirin within 4 hours of severe chest pain onset. We created a synthetic cohort of adults ≥ 40 years old experiencing severe chest pain using 2019 US population estimates, AMI incidence, and sensitivity/specificity of chest pain for AMI. The number of annual deaths delayed was estimated using evidence from a large, randomized trial. We also estimated the years of life saved (YOLS), costs, and cost per YOLS. Initiating aspirin within 4 hours of severe chest pain onset delayed 13 016 (95% CI, 11 643-14 574) deaths annually, after accounting for deaths due to bleeding (963; 926-1003). This translated to an estimated 166 309 YOLS (149391-185 505) at the cost of $643 235 (633 944-653 010) per year, leading to a cost-effectiveness ratio of $3.70 (3.32-4.12) per YOLS. CONCLUSIONS: For <$4 per YOLS, self-administration of aspirin within 4 hours of severe chest pain onset has the potential to save 13 000 lives per year in the US population. Benefits of reducing deaths post-AMI outweighed the risk of bleeding deaths from aspirin 10 times over.

Tranexamic acid loaded in a physically crosslinked trilaminate dressing for local hemorrhage control: Preparation, characterization, and in-vivo assessment using two different animal models.

This work aimed at formulating a trilaminate dressing loaded with tranexamic acid. It consisted of a layer of 3 % sodium hyaluronate to initiate hemostasis. It was followed by a mixed porous layer of 5 % polyvinyl alcohol and 2 % kappa-carrageenan. This layer acted as a drug reservoir that controlled its release. The third layer was 5 % ethyl cellulose backing layer for unidirectional release of tranexamic acid towards the wound. The 3 layers were physically crosslinked by hydrogen bonding as confirmed by Infrared spectroscopy. Swelling and release studies were performed, and results proposed that increasing number of layers decreased swelling properties and sustained release of tranexamic acid for 8 h. In vitro blood coagulation study was performed using human blood and showed that the dressing significantly decreased coagulation time by 70.5 % compared to the negative control. In vivo hemostatic activity was evaluated using tail amputation model in Wistar rats. Statistical analysis showed the dressing could stop bleeding in a punctured artery of the rat tail faster than the negative control by 59 %. Cranial bone defect model in New Zealand rabbits was performed to check for bone hemostasis and showed significant decrease in the hemostatic time by 80 % compared to the control.

Anticoagulation stewardship: Improving adherence to clinical guidelines and reducing overuse of venous thromboembolism prophylaxis in hospitalized medical patients.

Adherence to guideline recommendations for venous thromboembolism prophylaxis (VTE) in hospitalized medical patients is suboptimal despite national policies and institutional interventions. The aim of this quality improvement project was to improve adherence to guidelines and decrease the overuse of VTE prophylaxis in order to reduce the institutional cost for heparins. A multidisciplinary anticoagulation stewardship program (ACSP) using the audit and feedback strategy was implemented on the medicine inpatient units at a teaching hospital in Canada. The primary outcome measure was a comparison, pre and post introduction of the ACSP, of the costs per 6-month period for prophylactic dose enoxaparin and unfractionated heparin on the medicine units. The balancing measures were the 90-day VTE rate and major bleeding rate during the hospitalization. Six months after the implementation of the ACSP, the cost was decreased by >50 % without any observed negative impact on patient safety. This study demonstrates the potential for anticoagulation stewardship programs to optimize the use of VTE prophylaxis and reduce the associated costs and risks.

Health-related quality of life and healthcare costs of symptoms and cardiovascular disease events in patients with atrial fibrillation: a longitudinal analysis of 27 countries from the EURObservational Research Programme on Atrial Fibrillation general long-term registry.

AIMS: We examine the effects of symptoms and cardiovascular disease (CVD) events on health-related quality of life (HRQOL) and healthcare costs in a European population with atrial fibrillation (AF). METHODS AND RESULTS: In the EURObservational Research Programme on AF long-term general registry, AF patients from 250 centres in 27 European countries were enrolled and followed for 2 years. We used fixed effects models to estimate the association of symptoms and CVD events on HRQOL and annual healthcare costs. We found significant decrements in HRQOL in AF patients in whom ST-segment elevation myocardial infarction (STEMI) [-0.075 (95% confidence interval -0.144, -0.006)], angina or non-ST-elevation myocardial infarction (NSTEMI) [-0.037 (-0.071, -0.003)], new-onset/worsening heart failure [-0.064 (-0.088, -0.039)], bleeding events [-0.031 (-0.059, -0.003)], thromboembolic events [-0.071 (-0.115, -0.027)], mild symptoms [0.037 (-0.048, -0.026)], or severe/disabling symptoms [-0.090 (-0.108, -0.072)] occurred during the follow-up. During follow-up, annual healthcare costs were associated with an increase of €11 718 (€8497, €14 939) in patients with STEMI, €5823 (€4757, €6889) in patients with angina/NSTEMI, €3689 (€3219, €4158) in patients with new-onset or worsening heart failure, €3792 (€3315, €4270) in patients with bleeding events, and €3182 (€2483, €3881) in patients with thromboembolic events, compared with AF patients without these events. Healthcare costs were primarily driven by inpatient costs. There were no significant differences in HRQOL or healthcare resource use between EU regions or by sex. CONCLUSION: Symptoms and CVD events are associated with a high burden on AF patients and healthcare systems throughout Europe.

Percutaneous left atrial appendage occlusion and risk of stroke, hospitalized bleeding and death in Medicare beneficiaries.

PURPOSE: Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA2DS2-VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death. METHODS: Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA2DS2-VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used. RESULTS: Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years. CONCLUSION: In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications.

Cost-Effectiveness of Recombinant Factor IX Fc Prophylaxis and Recombinant Factor IX On-Demand Treatment in Patients with Haemophilia B Without Inhibitors.

INTRODUCTION: Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophilia B. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or 'on-demand' (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophilia B without inhibitors in the Italian healthcare setting. METHODS: A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12 years) with haemophilia B (FIX level of ≤ 2 IU/dL) without inhibitors. Model inputs were derived from the pivotal phase 3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio. RESULTS: rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (- 682.29) and surgeries (- 0.39) compared with rFIX on-demand. CONCLUSIONS: rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophilia B. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophilia B.

Converting IMPROVE bleeding and VTE risk assessment models into a fast-and-frugal decision tree for optimal hospital VTE prophylaxis.

ABSTRACT: Current hospital venous thromboembolism (VTE) prophylaxis for medical patients is characterized by both underuse and overuse. The American Society of Hematology (ASH) has endorsed the use of risk assessment models (RAMs) as an approach to individualize VTE prophylaxis by balancing overuse (excessive risk of bleeding) and underuse (risk of avoidable VTE). ASH has endorsed IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) risk assessment models, the only RAMs to assess short-term bleeding and VTE risk in acutely ill medical inpatients. ASH, however, notes that no RAMs have been thoroughly analyzed for their effect on patient outcomes. We aimed to validate the IMPROVE models and adapt them into a simple, fast-and-frugal (FFT) decision tree to evaluate the impact of VTE prevention on health outcomes and costs. We used 3 methods: the "best evidence" from ASH guidelines, a "learning health system paradigm" combining guideline and real-world data from the Medical University of South Carolina (MUSC), and a "real-world data" approach based solely on MUSC data retrospectively extracted from electronic records. We found that the most effective VTE prevention strategy used the FFT decision tree based on an IMPROVE VTE score of ≥2 or ≥4 and a bleeding score of <7. This method could prevent 45% of unnecessary treatments, saving ∼$5 million annually for patients such as the MUSC cohort. We recommend integrating IMPROVE models into hospital electronic medical records as a point-of-care tool, thereby enhancing VTE prevention in hospitalized medical patients.

Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban.

Importance: Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. Objective: To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Exposures: Diltiazem and metoprolol. Main Outcomes and Measures: The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. Results: The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). Conclusions and Relevance: In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Structured benefit-risk assessment for enoxaparin, in the context of its label extension, for the extended treatment of deep vein thrombosis and pulmonary embolism, and prevention of its recurrence in patients with active cancer.

PURPOSE: Guidelines recommend low-molecular-weight heparins (LMWHs) for patients with cancer-associated thrombosis. However, until recently, only dalteparin and tinzaparin were approved in the European Economic Area (EEA) for these patients. This study compares the benefit-risk profile of enoxaparin with dalteparin and tinzaparin for the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence in adult patients with active cancer. METHODS: A semi-quantitative structured benefit-risk assessment was conducted for the label-extension application of enoxaparin based on the benefit-risk action team descriptive framework: define decision context; determine key benefit and risk outcomes; identify data sources; extract data; interpret results. RESULTS: The key benefits were defined as reduced all-cause mortality and venous thromboembolism (VTE) recurrence (including symptomatic DVT, fatal PE or non-fatal PE); the key risks were major and non-major bleeding of clinical significance, and heparin-induced thrombocytopenia (HIT). Enoxaparin demonstrated comparable effects for the reduction of VTE recurrence and all-cause mortality versus other EEA-approved LMWHs (dalteparin, tinzaparin). There was no evidence of a significant difference between enoxaparin and the comparator groups with regard to incidence of major and non-major bleeding. The data on HIT were too limited to assess the difference between the two groups. CONCLUSIONS: The assessment demonstrated a favourable benefit-risk profile for enoxaparin similar to that of other EEA-approved LMWHs for the treatment of DVT and PE and the prevention of recurrence in patients with active cancer and thus supported the label-extension approval.

Development and Validation of Machine Learning Algorithms to Predict 1-Year Ischemic Stroke and Bleeding Events in Patients with Atrial Fibrillation and Cancer.

In this study, we leveraged machine learning (ML) approach to develop and validate new assessment tools for predicting stroke and bleeding among patients with atrial fibrillation (AFib) and cancer. We conducted a retrospective cohort study including patients who were newly diagnosed with AFib with a record of cancer from the 2012-2018 Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The ML algorithms were developed and validated separately for each outcome by fitting elastic net, random forest (RF), extreme gradient boosting (XGBoost), support vector machine (SVM), and neural network models with tenfold cross-validation (train:test = 7:3). We obtained area under the curve (AUC), sensitivity, specificity, and F2 score as performance metrics. Model calibration was assessed using Brier score. In sensitivity analysis, we resampled data using Synthetic Minority Oversampling Technique (SMOTE). Among 18,388 patients with AFib and cancer, 523 (2.84%) had ischemic stroke and 221 (1.20%) had major bleeding within one year after AFib diagnosis. In prediction of ischemic stroke, RF significantly outperformed other ML models [AUC (0.916, 95% CI 0.887-0.945), sensitivity 0.868, specificity 0.801, F2 score 0.375, Brier score = 0.035]. However, the performance of ML algorithms in prediction of major bleeding was low with highest AUC achieved by RF (0.623, 95% CI 0.554-0.692). RF models performed better than CHA2DS2-VASc and HAS-BLED scores. SMOTE did not improve the performance of the ML algorithms. Our study demonstrated a promising application of ML in stroke prediction among patients with AFib and cancer. This tool may be leveraged in assisting clinicians to identify patients at high risk of stroke and optimize treatment decisions.

Benefit and risk of oral anticoagulant initiation strategies in patients with atrial fibrillation and cancer: a target trial emulation using the SEER-Medicare database.

Oral anticoagulants (OACs) are recommended for patients with atrial fibrillation (AFib) having CHA2DS2-VASc score ≥ 2. However, the benefits of OAC initiation in patients with AFib and cancer at different levels of CHA2DS2-VASc is unknown. We included patients with new AFib diagnosis and a record of cancer (breast, prostate, or lung) from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database (n = 39,915). Risks of stroke and bleeding were compared between 5 treatment strategies: (1) initiated OAC when CHA2DS2-VASc ≥ 1 (n = 6008), (2) CHA2DS2-VASc ≥ 2 (n = 8694), (3) CHA2DS2-VASc ≥ 4 (n = 20,286), (4) CHA2DS2-VASc ≥ 6 (n = 30,944), and (5) never initiated OAC (reference group, n = 33,907). Confounders were adjusted using inverse probability weighting through cloning-censoring-weighting approach. Weighted pooled logistic regressions were used to estimate treatment effect [hazard ratios (HRs) and 95% confidence interval (95% CIs)]. We found that only patients who initiated OACs at CHA2DS2-VASc ≥ 6 had lower risk of stroke compared without OAC initiation (HR 0.64, 95% CI 0.54-0.75). All 4 active treatment strategies had reduced risk of bleeding compared to non-initiators, with OAC initiation at CHA2DS2-VASc ≥ 6 being the most beneficial strategy (HR = 0.49, 95% CI 0.44-0.55). In patients with lung cancer or regional/metastatic cancer, OAC initiation at any CHA2DS2-VASc level increased risk of stroke and did not reduce risk of bleeding (except for Regimen 4). In conclusion, among cancer patients with new AFib diagnosis, OAC initiation at higher risk of stroke (CHA2DS2-VASc score ≥ 6) is more beneficial in preventing ischemic stroke and bleeding. Patients with advanced cancer or low life-expectancy may initiate OACs when CHA2DS2-VASc score ≥ 6.

Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study.

INTRODUCTION: Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS: A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS: In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION: Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Certain treatments for liver cancer can cause serious side effects, including bleeding, blood clots, brain injury (encephalopathy), or increased blood flow to the liver (portal hypertension). We used an insurance database to find out how often these events, known as clinically significant events, occurred in people with liver cancer who were given treatments that target the immune system (immunotherapy) or specific proteins involved in cancer growth and survival (targeted therapy). The study included 1379 patients treated with atezolizumab (immunotherapy) plus bevacizumab (targeted therapy), or lenvatinib or sorafenib alone (both targeted therapies), as their first treatment. Clotting and bleeding were the most common clinically significant events in patients treated with atezolizumab plus bevacizumab, whereas clotting and encephalopathy were the most common clinically significant events with lenvatinib, and encephalopathy and portal hypertension were the most common clinically significant events with sorafenib. On average, for every 100 patients treated for 1 year, there were more than 50 of each of these events. Average healthcare costs per patient per month ranged from around $29,000 to around $36,000 in the three different treatment groups, and were higher in people who had at least one clinically significant event. These results suggest that clinically significant events are common in people with liver cancer who are given various types of treatment. As well as raising concerns for patient safety, these events result in higher costs to healthcare systems. Therefore, newer treatments that are less likely to cause clinically significant events, while improving survival in patients with liver cancer, are needed.