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To examine the association between inferior vena cava (IVC) diameter and postpartum blood loss and assess whether IVC diameter is a useful marker in the evaluation of intravascular volume status in women with postpartum hemorrhage (PPH).This was a prospective case-control study conducted in a university medical teaching center in Afula, Israel, between November 2018 and March 2020. The study cohort consisted of women with a singleton pregnancy who delivered vaginally at term. The PPH group included women diagnosed with PPH based on visually estimated blood loss of 1000 mL or more at the time of enrolment. Hemodynamically unstable women or women with major bleeding at the time of diagnosis were not included. The control group consisted of women with an uneventful fourth stage of labor. IVC diameter was measured using transabdominal ultrasonography during inspiration (IVCi diameter) and expiration (IVCe diameter), and the collapsibility index was calculated ((IVCe - IVCi)/IVCe × 100). The primary outcome was the percentage difference in IVC diameter and collapsibility index between the PPH group and controls. The performance of the IVC collapsibility index in the prediction of the need for blood transfusion in women with PPH was assessed. In order to demonstrate a difference of 20% with a power of 80% and alpha of 0.05, 108 women, at a ratio of 1:2 in the study and control groups, respectively, were needed.Overall, 36 and 72 women were included in the final analysis in the PPH and control groups, respectively. IVCi and IVCe diameters were significantly smaller in the PPH group (0.93 ± 0.30 cm and 1.26 ± 0.32 cm, respectively) than in controls (1.42 ± 0.31 cm and 1.75 ± 0.28 cm, respectively) (P = 0.001 for both). The percentage reductions in IVCi and IVCe diameters in the PPH group compared with controls were 35.0% and 28.0%, respectively. IVC collapsibility index was increased significantly, by 42.9% (26.04 ± 8.67% vs 18.15 ± 5.07%; P = 0.001) in the PPH group compared with controls. IVC collapsibility index was a significant predictor of the need for blood transfusion and correctly predicted 81% of cases. Logistic regression analysis demonstrated that IVC collapsibility index was also a significant predictor of a drop in hemoglobin level of ≥ 2 g/dL (P = 0.001).IVC diameter changes in response to postpartum blood loss. Measurement of IVC diameter using transabdominal ultrasonography is an objective and useful non-invasive method for the early evaluation of intravascular volume status in women with PPH and for the prediction of cases that might require blood transfusion. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background Anemia is a common comorbidity in patients with atrial fibrillation (AF). Reports on the association of anemia and adverse events in patients with AF, especially from Asia, are limited. Methods and Results Based on data from the Chinese Atrial Fibrillation Registry Study (CAFR), a total of 18,106 AF patients enrolled between August 2011 and December 2018 had hemoglobin (Hb) values recorded at baseline. Patients were classified into three groups according to Hb levels: 15,606 patients (86.2%) into the no anemia group (male Hb≥130 g/L; female Hb≥120 g/L), 1800 (9.9%) with mild anemia (male 110≤Hb

Objective The optimal intensity of anticoagulation for adult patients supported with extracorporeal membrane oxygenation (ECMO) remains uncertain. The objective of this study was to evaluate the effectiveness and safety of two anticoagulation protocols using conventional (0.3-0.7 IU/ml) versus restricted (0.2-0.5 IU/ml) anti-factor Xa (anti-Xa) targets for the management of unfractionated heparin (UFH) in adult ECMO patients. Methods This retrospective before-after cohort study compared two groups of ECMO patients who received UFH for at least 24-h from March 2016 to May 2019. The primary outcome was the composite rate of major bleeding or thrombotic events per ECMO day. Secondary outcomes included the mean amount of blood products transfused per ECMO day, the proportion of patients who were within the target anti-Xa at 24-h, the time to achieve target anti-Xa, and the number of heparin infusion adjustments to reach target anti-Xa. Results Forty-one patients were included in this analysis (conventional, n = 25; restricted, n = 16). There was no difference in the composite rate of major bleeding or thrombotic events per ECMO day (p = .090). The restricted group had lower rates of packed red blood cells (pRBC) transfusion per ECMO day (mean 1 ± 1 vs 3 ± 2 units, p = .003) and required fewer heparin infusion adjustments to reach the target (p = .007). There was no difference between the groups in the number of patients who achieved target anti-Xa at 24-h (p = .940). Conclusion In adult ECMO patients, anticoagulation with a restricted anti-Xa target was associated with lower pRBC transfusions and did not provoke an excess of thrombotic events.

BACKGROUND AND AIM The RHEMITT score (Renal disease; Heart failure; Endoscopic findings; Major bleeding; Incomplete SBCE; Tobacco; Treatment by enteroscopy) was the first score to accurately predict the individual risk of small bowel rebleeding after capsule endoscopy (SBCE). The aim of the study is on the prospective validation of the RHEMITT score. METHODS Cohort of consecutive patients with mid-gastrointestinal bleeding (MGIB) submitted to SBCE and followed prospectively, during at least 12 months, since 2017 until 2020. Rebleeding was defined as an overt bleeding event (melena or hematochezia) or a hemoglobin decrease of at least 2 g/dL. The RHEMITT score was calculated for each patient and the rebleeding rates compared. The performance of the score was tested by calculating the area under curve of the receiver operator characteristic curve. A rebleeding-free survival was assessed, corresponding to the period between the date of SBCE and the date of the first post-SBCE rebleeding event. RESULTS We included 162 patients, 102 (62.9%) were female, with a mean age of 64 years old. The sensitivities and specificities of the score grades for predicting rebleeding were as following: for low-risk patients, 0% (0-10%) and 28.8% (21.1-36.5%); for intermediate-risk patients, 23.3% (8.2-38.4%) and 72% (64.3-79.7%); for high-risk patients, 76.7% (61.6-91.8%) and 99.2% (97.7-100%), corresponding to an area under curve of the receiver operator characteristic of 0.988 (P

PURPOSE This study aims to validate major bleeding (MB) cases within a cohort of new users of direct oral anticoagulants (DOACs) in Electronic health records (EHRs) from primary care in Spain (BIFAP), introducing more efficient techniques and automating the process of validation in the pharmacoepidemiologic research with EHR data as much as possible. METHODS Registered bleedings were identified in a cohort of new users of DOACs in BIFAP using ICPC 2 and ICD 9 codes; we ascertained these bleedings as MB through a validation strategy based on the MB definition from the International Society on Thrombosis and Hemostasis, which used hospitalization and critical localization as proxies. We assessed hospitalization with hospital discharge information (only available for some years and regions) and a free text-based algorithm created to identify hospitalization in EHR's clinical notes. Incidence rates (IR) of MB were evaluated by bleeding type. RESULTS The study cohort included 104 614 patients, with 274521.5 p-y of follow up. There were 6143 registered bleedings during the study period (519 intracranial bleeding - ICB, 4606 gastrointestinal bleeding - GIB, 1018 extracranial bleeding - ECB), from which 1679 were confirmed as MB (416 ICB, 1086 GIB, and 177 ECB). The free text-based semi-automatic algorithm had moderate recall (0.59), but high specificity (0.99), and precision (0.94). CONCLUSION The combination of hospitalization and critical localization is a valid approach to validate MB in EHRs with incomplete information. The use of more automatic methods for case validation instead of manual review of clinical notes is favored.

Background Patients with atrial fibrillation (AF) usually have a heterogeneous co‐morbid history, with dynamic changes in risk factors impacting on multiple adverse outcomes. We investigated a large prospective cohort of patients with multimorbidity, using a machine‐learning approach, accounting for the dynamic nature of comorbidity risks and incident AF. Methods Using machine‐learning, we studied a prospective US cohort using medical/pharmacy databases of 1 091 911 patients, with an incident AF cohort of 14 078 and non‐AF cohort of 1 077 833 enrolled in the 4‐year study. Five incident clinical outcomes (heart failure, stroke, myocardial infarction, major bleeding, and cognitive impairment) were examined in relationship to AF status (AF vs non‐AF), diverse multi‐morbid (conditions and medications) history, and demographic parameters (age and gender), with supervised machine‐learning techniques. Results Complex inter‐relationships of various comorbidities were uncovered for AF cases, leading to 6‐fold higher risk of heart failure relative to the non‐AF cohort (OR 6.02, 95% CI 5.72‐6.33), followed by myocardial infarction (OR=2.68), stroke (OR=2.19), and major bleeding (OR=1.36). Supervised machine learning algorithms on the original populations yielded comparable results for both neural network and logistic regression algorithms in terms of discriminant validity, with c‐indexes for incident adverse outcomes: heart failure (0.924, 95%CI 0.923‐0.925), stroke (0.871, 95%CI 0.869‐0.873), myocardial infarction (0.901, 95% CI 0.899‐0.903), major bleeding (0.700, 95%CI 0.697‐0.703), and cognitive impairment (0.919, 95% CI 0.9170.921). External calibration of all models demonstrated a good fit between the predicted probabilities and observed events. Decision curve analysis demonstrated that the obtained models were much more clinically useful than the “treat all” strategy. Conclusions Complex multimorbidity relationships uncovered using a machine learning approach for incident AF cases have major consequences for integrated care management, with implications for risk stratification and adverse clinical outcomes. This approach may facilitate automated approaches in the presence of multimorbidity, potentially helping decision making., External calibration for five predictive models (a – heart failure; b – stroke; c – myocardial infarction; d – major bleeding; e – cognitive impairment).

Aims: The net benefit of oral anticoagulants (OACs) in atrial fibrillation (AF) is poorly understood. We aimed to determine the NNT for net effect (NNT net) using calculator of absolute stroke risk (CARS) in anticoagulated patients with AF in real-world and clinical trial cohorts. Methods: Post-hoc analysis of patient-level data from the real-world Murcia AF Project and AMADEUS clinical trial. Baseline risk of stroke was determined using CARS. The risk of stroke and major bleeding events with OAC were determined using the number of respective events at 1-year. NNT net was calculated as a reciprocal of the net effect of absolute risk reduction with OAC (NNT net = 1/(absolute risk reduction of stroke[ARR stroke] − absolute risk increase of major bleeding[ARI bleeding])). Results: In total, 3511 patients were included (1306 [37.2%] real-world patients and 2205 [62.8%] clinical trial participants). The absolute 1-year stroke risk was similar across both cohorts. In the real-world cohort, OAC was associated with a 4.0% ARR stroke, 25 NNT benefit, 1.0% ARI bleeding, 100 NNT harm and 34 NNT net. In the clinical trial cohort, OAC was associated with a 3.8% ARR stroke, 27 NNT benefit, 1.6% ARI bleeding, 63 NNT harm and 46 NNT net. In both cohorts, the NNT net was significantly lower in patients with an excess stroke risk of ≥2% by CARS. Conclusion: Overall, the NNT net approach in AF incorporates information regarding baseline risk of stroke and major bleeding, and relative effects of OAC with the potential to include multiple additional outcomes and weighting of events based on their perceived effects by individual patients.

International audience; Patients with acute venous thromboembolism (VTE) require anticoagulant therapy to prevent recurrent VTE and death, which exposes them to an inherent increased risk of bleeding. Identification of patients at high risk of bleeding, and mitigating this risk, is an essential component of the immediate and long-term therapeutic management of VTE. The bleeding risk can be estimated by either implicit judgment, weighing individual predictors (clinical variables or biomarkers), or by risk prediction tools developed for this purpose. Management of bleeding risk in clinical practice is, however, far from standardized. International guidelines are contradictory and lack clear and consistent guidance on the optimal management of bleeding risk. This report of the ISTH subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease summarizes the evidence on the prediction of bleeding in VTE patients. We systematically searched the literature and identified 34 original studies evaluating either predictors or risk prediction models for prediction of bleeding risk on anticoagulation in VTE patients. Based on this evidence, we provide recommendations for the standardized management of bleeding risk in VTE patients.

Background: The effectiveness and safety of non-heparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT) are not fully established, and the optimal treatment strategy is unknown. In a systematic review and meta-analysis, we aimed to determine precise rates of platelet recovery, new or progressive thromboembolism (TE), major bleeding, and death for all non-heparin anticoagulants and to study potential sources of variability. Methods: Following a detailed protocol (PROSPERO: CRD42020219027), EMBASE and Medline were searched for all studies reporting clinical outcomes of patients treated with non-heparin anticoagulants (argatroban, danaparoid, fondaparinux, direct oral anticoagulants [DOAC], bivalirudin, and other hirudins) for acute HIT. Proportions of patients with the outcomes of interest were pooled using a random-effects model for each drug. The influence of the patient population, the diagnostic test used, the study design, and the type of article was assessed. Findings: Out of 3’194 articles screened, 92 studies with 119 treatment groups describing 4’698 patients were included. The pooled rates of platelet recovery ranged from 74% (bivalirudin) to 99% (fondaparinux), TE from 1% (fondaparinux) to 7% (danaparoid), major bleeding from 1% (DOAC) to 14% (bivalirudin), and death from 7% (fondaparinux) to 19% (bivalirudin). Confidence intervals were mostly overlapping, and results were not influenced by patient population, diagnostic test used, study design, or type of article. Interpretation: Effectiveness and safety outcomes were similar among various anticoagulants, and significant factors affecting these outcomes were not identified. These findings support fondaparinux and DOACs as viable alternatives to conventional anticoagulants for treatment of acute HIT in clinical practice. Registration Information: PROSPERO: CRD42020219027. Funding Information: This study was supported by a research grant of the Swiss National Science Foundation (#179334). Declaration of Interests: Conflict-of-interest disclosure: M.N. received research grants from Bayer Healthcare. A.C. has served as a consultant for synergy and his institution has received research support on his behalf from alexion, Bayer, Novartis, novo Nordisk, Pfizer, Sanofi, spark, and Takeda. All other authors declare that no conflict of interest exists.

Introduction COVID‐19 predisposes patients to a higher risk of venous thromboembolism (VTE), although the extent of these implications is unclear and the risk of bleeding has been poorly evaluated. To date, no studies have reported long‐term outcomes of patients with COVID‐19 and VTE. Method Prospective observational study to evaluate long‐term (90 days or more) outcomes of patients diagnosed with VTE (PE, DVT of the extremities, or both) in the setting of COVID‐19. The main outcome of the study was a compound of major bleeding and death. Results The study comprised 100 patients (mean age 65 ± 13.9 years). At the time of VTE diagnosis, 66% patients were hospitalized, 34.8% of them in the ICU. Mean follow‐up was 97.9 ± 23.3 days. During the study period, 24% patients died and median time to death was 12 (IQR: 2.25‐20.75) days, 11% patients had major bleeding and median time to event was 12 (IQR: 5‐16) days. The cause of death was PE in 5% and bleeding in 2% of patients. There were no VTE recurrences. The main study outcome occurred in 29% patients. Risk of death or major bleeding was independently associated with ICU admission (HR 12.2; 95% CI 3.0‐48.3), thrombocytopenia (HR 4.5; 95% CI 1.2‐16.5), and cancer (HR 21.6; 95% CI 1.8‐259). Conclusion In patients with COVID‐19 and VTE, mortality and major bleeding were high and almost a third of deaths were VTE‐related. The majority of complications occurred in the first 30 days. ICU admission, thrombocytopenia, and cancer are risk factors for poor prognosis.

Background The uptake rate of non-vitamin K oral anticoagulants (NOAC) for the treatment of non-valvular atrial fibrillation (AF) was far lower in the Netherlands (NL) compared to Belgium (BE). Also, patients on VKA in NL were treated with a higher target international normalized ratio (INR) range of 2.5 to 3.5. Objectives To explore the effect of these differences on thromboembolism (TE) and bleeding. Methods Data from the GARFIELD-AF registry was used. Patients with new-onset AF and >= 1 investigator-determined risk factor for stroke were included between 2010 and 2016. Event rates from 2 years of follow-up were used. Results In NL and BE, 1186 and 1705 patients were included, respectively. Female sex (42.3% vs 42.2%), mean age (70.7 vs 71.3 years), CHA(2)DS(2)-VASc (3.1 vs 3.1), and HAS-BLED score (1.4 vs 1.5) were comparable between NL and BE. At diagnosis in NL vs BE, 72.1% vs 14.6% received vitamin K antagonists (VKA) and 17.8% vs 65.5% NOACs, varying greatly across cohorts. Mean INR was 2.9 (+/- 1.0) and 2.4 (+/- 1.0) in NL and BE, respectively. Event rates per 100 patient-years in NL and BE, respectively, of all-cause mortality (3.38 vs 3.90; hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65-1.15), ischemic stroke/TE (0.82 vs 0.72; HR 1.14, 95% CI 0.62-2.11), and major bleeding (2.06 vs 1.54; HR 1.33, 95% CI 0.89-1.99) did not differ significantly. Conclusions In GARFIELD-AF, despite similar characteristics, patients on anticoagulants were treated differently in NL and BE. Although the rate of major bleeding was 33% higher in NL, variations in bleeding, mortality, and TE rates were not statistically significant.

OBJECTIVES To determine whether renal transplant diagnoses substantially change when 2 biopsy sites are chosen and whether contrast-enhanced ultrasound (CEUS) has value for targeting the second site. METHODS We prospectively enrolled 40 patients undergoing ultrasound-guided renal transplant biopsy within 2 years of transplant: 20, surveillance; and 20, for cause. A CEUS examination was performed to identify cortical regions with subjectively altered flow. One biopsy was performed at the operator-preferred (primary) site regardless of CEUS findings. Another biopsy was done at a second location, either targeted to an area in which CEUS perfusion findings differed from the primary site (targeted) or at a random location (secondary) if no other area differed. Specimens were randomly labeled A or B; pathologists were blinded to the CEUS result and biopsy location. Location-specific CEUS assessments were recorded. Pathologic results were compared, including acute and chronic Banff scores and any new findings from the targeted or secondary biopsy. RESULTS Forty patients were enrolled between January 2016 and December 2018. No location-specific pathologic differences correlated with differences in CEUS assessments. The second biopsy provided additional information that changed management in 4 of 40 patients (10.0% [95% confidence interval, 2.8%-23.7%]). Major bleeding complications occurred in 3 of 40 (7.5%) patients. CONCLUSIONS Contrast-enhanced ultrasound targeting was not useful. Major bleeding complications were higher than expected, possibly due to the additional biopsy away from the operator-preferred location. Obtaining a second renal transplant biopsy from a substantially different area than the initial operator-preferred location provided additional clinically useful information in 10% of patients.

Objectives This study aimed to assess the feasibility, efficacy, and safety of a novel percutaneous postprocedure closure technique for large arterial sheath removal with the use of two Perclose ProGlide (Abbott Vascular Devices, Redwood City, CA) devices. Background Postprocedural closing of large-bore arteriotomies using the Perclose system can be difficult given the subsequent inability of the device to capture sufficient wall tissue. Methods Our study was a single-center retrospective analysis of 22 consecutive patients who underwent large arteriotomy closure via the postclosure technique with a 12-16-Fr sheath. Efficacy endpoints included successful deployment of the system and hemostasis. Safety endpoints included the incidence of major or minor vascular complications as defined by the Vascular Academic Research Consortium-2 (VARC-2) definitions at 30-day follow-up. Results The postclosure technique resulted in 100% technical success rate and no postprocedural bleeding or vascular complications. Conclusion Postclosure technique is a safe, highly effective, and feasible percutaneous method to achieve large-bore arteriotomy hemostasis with low rates of major bleeding or vascular complications and favorable early outcome.

Aims Major bleeding events in heart failure (HF) patients are poorly described. We sought to investigate the importance of major bleeding and its impact on outcomes in HF patients. Methods and results We analysed incident bleeding and ischaemic events during a 3 year follow‐up in 2910 HF outpatients included in a prospective multicentre registry. Major bleeding was defined as a Type ≥3 bleed using the Bleeding Academic Research Consortium definition. Ischaemic event was a composite of ischaemic stroke and myocardial infarction. Events were adjudicated by a blinded committee. At inclusion, most patients (89%) received at least one antithrombotic: anticoagulation (53.9%) and/or antiplatelet therapy (46.2%). Bleeding occurred in 111 patients {3 year cumulative incidence: 3.6% [95% confidence interval (CI) 3.0–4.3]} and ischaemic events in 102 patients [3 year cumulative incidence: 3.3% (95% CI 2.7–4.0)]. Most bleedings were Bleeding Academic Research Consortium 3a (32.5%) or 3b (31.5%). Most frequent sites of bleeding were gastrointestinal (40.6%) and intracranial (27.9%). Variables associated with bleeding were atrial fibrillation [hazard ratio (HR) = 2.63 (95% CI 1.66–4.19), P

To investigate the association of extremes in bodyweight (EBW) and outcomes in patients with acute venous thromboembolism (VTE). Recurrent VTE, major bleeding, and clinically relevant non-major bleeding were compared between patients with bodyweight 60 kg, 60-120 kg, and 120 kg.Consecutive patients enrolled in the Mayo Clinic VTE Registry (03/28/2013-8/31/2019) with acute VTE were followed prospectively. Patient status was assessed in person, by mailing a written questionnaire, or by a scripted phone interview.Among 2577 patients with weight ranging from 27.0 kg to 263.2 kg, 2123 (82%) had a bodyweight between 60 and 120 kg, 223 (8.7%) had bodyweight 60 kg, and 230 (8.9%) had bodyweight 120 kg. Patients with bodyweight 60 kg treated with DOACs had higher 3- and 6-month incidence of major bleeding compared to the bodyweight 60-120kg group (4.4% vs 1.1%, P = .03, and 4.4% vs 1.4%, P = .05, respectively). Patients with bodyweight 120 kg and cancer on rivaroxaban had higher VTE recurrence compared to bodyweight 60-120kg group (P = .01).Treatment of acute VTE is associated with a higher incidence of bleeding in patients with bodyweight 60 kg. A higher VTE recurrence rate occurred only in cancer patients with bodyweight 120 kg on rivaroxaban.

International audience; Aims: The objective was to compare major bleeding risk of direct oral anticoagulants (DOACs; per type and dose) with vitamin K antagonists (VKAs), irrespective of indication, using real-world data.Methods: A population-based prospective cohort study, using the French national health data system (SNIIRAM), identified 47 469 adults living within 5 well-defined geographical areas, who were new users of oral anticoagulants in the period 2013-2015: 20 205 VKA users, 19 579 rivaroxaban users, 4225 dabigatran users and 3460 apixaban users. From all emergency departments within these areas, clinical data for all adults referred for bleeding was collected and medically validated. The databases were linked for common key variables. The main outcome measure was major bleeding: intracranial haemorrhage, major gastrointestinal bleeding and other major bleeding events. Hazard ratios were derived from adjusted Cox proportional hazard models. We used propensity score weighting as a sensitivity analysis, with separate analyses according to indications (atrial fibrillation or venous thromboembolism).Results: Compared to VKAs, high and low-dose DOACs were associated with a reduced risk of intracranial haemorrhage (adjusted hazard ratio 0.55, 95% confidence interval 0.37-0.82 and 0.54, 0.26-1.12 respectively), and a reduced risk of other major bleeding events (0.41, 0.29-0.58 and 0.41, 0.22-0.79 respectively), irrespective of duration and indication. Neither DOAC dose evidenced any significant difference from VKAs in terms of risk of major gastrointestinal bleeding.Conclusion: There is a clear benefit of using DOACs with regard to intracranial haemorrhage. The study provides new insight into major gastrointestinal and other major bleeding events.

Background To date, there has been no study that compares the efficacy and safety of warfarin in atrial fibrillation (AF) patients with Evaluated Heartvalves, Rheumatic or Artificial (EHRA) type 2 valvular heart disease (VHD). This study was conducted to determine the optimal INR in these patients. Methods This retrospective study enrolled AF patients with EHRA type 2 VHD receiving warfarin in Central Chest Institute of Thailand between January 2016 and December 2018. The incidence density of thromboembolic or bleeding events was calculated. The International normalized ratio (INR) was classified into six groups (less than 1.50, 1.50 to 1.99, 2.00 to 2.49, 2.50 to 2.99, 3.00 to 3.49, and 3.50 or more). The optimal INR level was defined as the lowest incidence density of thromboembolic events and bleeding complications. Results A total of 200 AF patients with EHRA type 2 VHD receiving warfarin were enrolled, contributing to 289 patient‐years of observation period. There were 13 thromboembolic events (4.5 per 100 patient‐years) and 16 bleeding events (5.5 per 100 patient‐years). The incidence density of thromboembolic events was significantly increased in the INR level below 2.00 (P = .03), while the INR level of 3.50 or more was significantly increased in the incidence density of major bleeding events (P = .03). Total bleeding and minor bleeding were increased significantly in INR level of 2.50 or more (P = .04). Conclusions The INR of 2.00 to 2.49 was appeared to be associated with the lowest incidence density of thromboembolic and bleeding events in these patients., This retrospective study enrolled AF patients with EHRA type 2 VHD receiving warfarin. The INR of 2.00 to 2.49 was appeared to be associated with the lowest incidence density of thromboembolic and bleeding events in these patients.

Background Patients with atrial fibrillation (AF) and chronic kidney disease represent a high‐risk group for thromboembolism and bleeding. Aims To explore the relationship between kidney function changes and outcomes of stroke/systemic embolism (SE), major bleeding and all‐cause death in anticoagulated AF patients participating in the BOREALIS trial comparing efficacy and safety of once‐weekly s.c. idrabiotaparinux to that of warfarin. Methods Changes in kidney function by estimated glomerular filtration rate (eGFR) were calculated using the Chronic Kidney Disease Epidemiology Collaboration equation in 2765 AF patients. Trial adjudicated outcomes were determined. Results After a mean follow‐up of 394 days, in 94.4% of the included patients kidney function changed ranging from −30 mL/min to 30 mL/min. The incidence of stroke/SE and major bleeding was similar between patients with deteriorated (reduction in eGFR from baseline over follow‐up) and preserved kidney function change (increase or no change in eGFR from baseline over follow‐up) [stroke/SE: incidence rate (IR): 1.33%/year vs 1.80%/year; hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.41‐1.32, P = .30; major bleeding: IR 1.63%/year vs 1.49%/year, HR 1.10, 95% CI 0.61‐1.97, P = .76]. On Cox regression analysis, patients with deteriorated kidney function were at higher risk for all‐cause death, compared to patients with preserved kidney function (HR: 1.64, 95% CI: 1.02‐2.63, P = .04). Conclusion In the BOREALIS trial, the risk of adjudicated stroke/SE, major bleedings, and all‐cause death was not related to mild‐moderate follow‐up changes in kidney function (±30 mL/min). The risk of all‐cause death was significantly increased in AF patients with abruptly deteriorating kidney function., Uncertainty exists among specialists on the best use of anticoagulation in AF patients with concomitant chronic kidney disease, particularly since kidney function may deteriorate in those taking anticoagulation, especially warfarin. Our analysis showed that all‐cause mortality was significantly higher in anticoagulated AF patients whose kidney function abruptly decreased over the study treatment period. The risk of thromboembolism and major bleedings was not related to mild‐moderate changes in kidney function (±30 mL/min).

Background: Rivaroxaban was reported as effective as traditional therapies for the acute treatment of venous thromboembolism (VTE) with fewer major bleeding complications in the seminal Einstein program and is now a recommended option for the treatment of VTE around the world. Objective: To report the safety and efficacy of rivaroxaban in daily care for the management of acute VTE in the United Kingdom. Patients/Method: The FIRST registry is a UK-only, multicenter, noninterventional, observational VTE study (NCT 02248610). Consecutive patients diagnosed with acute VTE, managed with rivaroxaban, were recruited and followed for up to 5 years. The primary outcomes were treatment-emergent symptomatic objectively diagnosed recurrent VTE, major and clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Results: A total of 1262 participants were recruited between 2014 and 2018. Participants were heterogeneous, with age range 18 to 95 years, weight 35 to 234 kg, and maximum body mass index 64.4 kg/m 2. The median duration of treatment exposure was 135 days (interquartile range [IQR], 84-307) and overall follow-up 497 days (IQR, 175-991). There were seven episodes of symptomatic VTE recurrence, 0.6%, (0.74/100 patient-years; 95% confidence interval [CI], 0.19-1.28). There were 79 of 1239 (6.4%), 8.66 of 100 patient-years (95% CI, 6.90-10.73) first episodes of major or CRNMB, which were most frequently reported by women aged

Sequential analysis is used in clinical trials and postmarket drug safety surveillance to prospectively monitor efficacy and safety to quickly detect benefits and problems, while taking the multiple testing of repeated analyses into account. When there are multiple outcomes, each one may be given a weight corresponding to its severity. This paper introduces an exact sequential analysis procedure for multiple weighted binomial end points; the analysis incorporates a drug’s combined benefit and safety profile. It works with a variety of alpha spending functions for continuous, group, or mixed group-continuous sequential analysis. The binomial probabilities may vary over time and do not need to be known a priori. The new method was implemented in the free R Sequential package for both one- and two-tailed sequential analysis. An example is given examining myocardial infarction and major bleeding events in patients who initiated non-steroidal antiinflammatory drugs.

Background Although anticoagulation therapy could reduce the risk of strokes in patients with atrial fibrillation (AF), large‐scale investigations in the direct oral anticoagulant (DOAC) and AF catheter ablation (CA) era are lacking. Methods This study was designed as a prospective, multicenter, observational study and a total of 2113 patients from 22 institutions were enrolled in the Hyogo area. Results The mean age and CHADS2 score were 70.1 ± 10.8 years old and 1.5 ± 1.1, respectively. The follow‐up period was 355 ± 43 days. CA was performed in 614 (29%) and DOACs were prescribed in 1118 (53%) patients. Ischemic strokes/systemic embolisms (SEs) and major bleeding occurred in 13 (0.6%) and 17 (0.8%) patients, respectively. New onset dementia, hospitalizations for cardiac events, and all‐cause death occurred in eight (0.4%), 60 (2.8%), and 29 (1.4%) patients, respectively. A multivariate analysis demonstrated that persistent AF and the body weight (BW) were associated with ischemic strokes/SEs and major bleeding, respectively (persistent AF: hazard ratio, 9.57; 95%CI, 1.2‐74.0; P = .03; BW: hazard ratio, 0.94; 95%CI, 0.90‐0.99; P = .02). AFCA history was associated with the cardiac events (hazard ratio, 0.44; 95%CI, 0.20‐0.99; P = .04). Age was associated with new onset dementia (hazard ratio, 1.1; 95%CI, 1.0‐1.2; P = .03). Conclusions In the DOAC and CA era, the incidence of ischemic strokes/SEs, major bleeding and cardiac events could be dramatically reduced in patients with AF. However, some unsolved issues of AF management still remain especially in elderly patients with persistent AF and a low BW.

Background Left atrial appendage closure (LAAC) is an alternative to long-term anticoagulation for thromboembolic protection in patients with atrial fibrillation (AF) and high bleeding risk. Short-term Warfarin use following LAAC is well-studied, while data pertaining to novel oral anticoagulant (NOAC) use in this setting is less robust. Specifically, data regarding the safety and efficacy of postprocedural NOAC use in high-risk patients is lacking. Objective To compare the safety and efficacy of Warfarin and NOAC use in a high-risk patient population undergoing LAAC with the WATCHMAN device. Methods From November 2015 to October 2017, 97 patients underwent LAAC with the WATCHMAN device. All patients were discussed at a multidisciplinary meeting prior to device implantation. Longitudinal data were collected and analyzed for a composite endpoint of stroke and death at 8 months, and major bleeding at 3 and 6 months. Results Among the 90 patients included in the safety and efficacy analysis, 43 were prescribed Warfarin and 47 were prescribed NOACs. Baseline characteristics were comparable between study groups. There were no procedural complications and no significant differences in the incidence of death and stroke at 8 months or major bleeding at 3 and 6 months. Conclusion For patients with AF at high risk of both thromboembolic and hemorrhagic events, NOACs as compared to Warfarin, seem to be safe and effective for short-term anticoagulation following LAAC with the WATCHMAN device. Further validation in large randomized controlled trials is required.

To provide direct comparison between apixaban and rivaroxaban in patients with acute cancer-associated venous thromboembolism (Ca-VTE), consecutive patients treated with apixaban, rivaroxaban, or enoxaparin at Mayo Thrombophilia Clinic (March 1, 2013 to January 31, 2018)) were followed prospectively. The primary effectiveness outcome was venous thromboembolism (VTE) recurrence, and the secondary was mortality. The primary safety outcome was major bleeding, the secondary clinically relevant safety outcome was non-major bleeding (CRNMB), and the third a composite of major and CRNMB. There were 750 patients treated for acute Ca-VTE with apixaban (n = 224), rivaroxaban (n = 163), and enoxaparin (n = 363) within 14 days of diagnosis and for at least 3 months, or until study event. Recurrent VTE was diagnosed in 11 receiving apixaban, 7 receiving rivaroxaban (apixaban vs rivaroxaban hazard ratio (HR) 1.31, 95% confidence interval (95% CI) 0.51-3.36) and 17 in the enoxaparin receiving group (apixaban vs enoxaparin HR 1.14, 95% CI: 0.54, 2.42 and rivaroxaban vs enoxaparin HR 0.85, 95% Cl: 0.36, 2.06). There were 82 deaths in apixaban, 74 rivaroxaban (apixaban vs rivaroxaban HR 1.67, 95% Cl: 1.20, 2.33) and 171 in enoxaparin group (rivaroxaban vs enoxaparin HR 0.73, 95% Cl: 0.56, 0.96). Major bleeding occurred in 11 apixaban, 12 rivaroxaban (apixaban vs rivaroxaban HR 0.73, 95% Cl: 0.32, 1.66) and 21 enoxaparin group (apixaban vs enoxaparin HR 0.89, 95% Cl: 0.43, 1.84 and rivaroxaban vs enoxaparin HR 1.23, 95% Cl: 0.61, 2.50). The CRNMB rate was higher in rivaroxaban compared to apixaban (P = .03) and LMWH (P = .01) groups. Recurrence of VTE and major bleeding were similar in apixaban, rivaroxaban, and enoxaparin groups. Rivaroxaban was associated with higher CRNMB but lower mortality compared to apixaban and enoxaparin.

Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.

Essentials In 2016 the SSC proposed definitions for effective hemostasis in management of major bleeding. To validate these definitions, we studied the use in three large anticoagulant-reversal studies. Method agreement analysis and interobserver reliability showed at least acceptable agreement. Recommendations were made, advising use of the definition in hemostatic effectiveness studies. SUMMARY: Introduction In 2016 the Scientific and Standardization Subcommittee (SSC) on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis (ISTH) proposed criteria to evaluate the effectiveness of anticoagulant reversal in major bleeding management. Testing and validation of these criteria are required. Objective To investigate the method agreement, interobserver reliability and applicability of the ISTH proposed definitions for hemostatic effectiveness. Methods Patient data from three anticoagulant-antidote studies were used for hemostatic effectiveness assessment using the ISTH-proposed definitions and clinical opinion. For every patient a case document was produced. For each cohort, four adjudicators were asked to assess the hemostatic effectiveness independently on a case-by-case basis. Agreement between the two methods of hemostatic effectiveness assessment was calculated using Cohen's kappa (κ), with a calculated sample size of at least 73 cases. Results The full dataset consisted of 116 cases, resulting in 464 assessments. Method agreement in outcome was observed in 364 of 464 assessments (78.5%), resulting in κ of 0.634 (95% CI: 0.575-0.694), or "substantial agreement." Interobserver reliability analysis of the proposed definitions computed an overall agreement of 54.2% with κ of 0.312 ("fair agreement"). Discussion Method agreement analysis shows that the conclusions drawn using the ISTH definitions have "substantial agreement" with clinical opinion. Interobserver reliability analysis demonstrated acceptable agreement. In-depth analysis provided minor opportunities for further improvement and correct application of the definition. The definition is recommended to be used in all future studies evaluating hemostatic effectiveness, taking the suggested recommendations into account.

Objective We assessed the number of cases with delayed anticoagulation initiation, explored the reasons for the delay, and its impact on outcome in patients with acute venous thromboembolism (VTE) treated in an organized setting of treatment initiation and continuous, prospective follow‐up. Methods Patients with anticoagulation initiation delay >24 hours were identified within the cohort of patients with acute VTE enrolled in the Mayo Clinic Venous Thromboembolism Registry between 2013 and 2020. The reasons for treatment delay were explored by reviewing the electronic database. VTE recurrence, all‐cause mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) were compared to those with no anticoagulation delay. Results Of 2378 patients with acute VTE, 100 (4.2%) experienced an anticoagulation delay. We identified seven reasons for treatment delays: deferring anticoagulation initiation to specialists (n = 38), thrombocytopenia (n = 10), planned or recent procedure (n = 16), active or recent bleeding (n = 12), missed diagnosis (n = 7), logistics (n = 6), and patient decision (n = 4). In seven cases, no reason was identified. We identified modifiable reasons for anticoagulation delay in 55%. At 90‐day follow‐up, patients with anticoagulation delay had a higher rate of mortality and major bleeding. VTE recurrence and CRNMB were not statistically different compared to those without anticoagulation delay. After adjustment for age, weight, and cancer, hazard ratios (HRs) for VTE recurrence and major bleeding remained elevated but not to a statistically significant level. Conclusion In the setting of a highly organized system of anticoagulation initiation, the incidence of treatment delay is low. Yet most delays could be avoided. A low number of cases provide insufficient power to evaluate the clinical consequences of anticoagulation initiation delay; however, elevated HR for VTE recurrence and major bleeding suggest association and need for further investigation.

BACKGROUND Transcatheter aortic valve implantation related thrombocytopenia (TAVI-rTP) is an inevitable phenomenon. However, no study has been performed on TAVI-rTP in the current setting of extended clinical indications combined with technology improvements. METHODS Patients with severe symptomatic aortic stenosis who underwent transfemoral TAVI, from January 2016 to December 2019 were enrolled. RESULTS Two-hundred and one consecutive patients (mean age 81.1 ± 7.1 years, 96 men) enrolled. Platelet count was recorded before and after aortic valve implantation. Dropped platelet count (DPC) occurred in all but 11 patients who were included. Two groups were created: DPC

OBJECTIVES This study compares procedural and late clinical outcomes of left atrial appendage closure (LAAC) with Amplatzer devices as a single versus a combined procedure with other structural or coronary interventions. BACKGROUND Multiple cardiac conditions are frequent among elderly patients and invite simultaneous treatment to ensure a favorable patient outcomes. METHODS 559 consecutive patients (73.3��������11.1���years) underwent LAAC with Amplatzer devices at two centres (Bern and Zurich university hospitals, Switzerland) either as a single procedure or combined with other interventions. The primary safety endpoint was a composite of major peri-procedural complications and major bleeding at follow-up, the primary efficacy endpoint included stroke, systemic embolism, and cardiovascular/unexplained death. All event rates are reported per 100 patient-years. RESULTS In 263 single and 296 combined procedures with percutaneous coronary interventions (47.6%), closure of an atrial septal defect (8.4%) or a patent foramen ovale (36.5%), transcatheter aortic valve implantation (10.1%), mitral clipping (4.1%), atrial fibrillation ablation (8.8%), or another procedure (3.0%) were analyzed. Device success (96.6% [single] vs. 99.0% [combined], p��=��.08) did not differ between the groups. After a mean follow-up of 2.6��������1.5 vs. 2.5��������1.5���years and a total of 1,422 patient-years, the primary efficacy (40/677, 5.9% [single] vs. 37/745, 5.0% [combined]; HR, 1.2, 95% CI, 0.8-1.9, p��=��.44), as well as the primary safety endpoint (25/677, 3.7% vs 28/745, 3.8%; HR, 1.0, 95% CI, 0.6-1.8, p��=��.89) were comparable. CONCLUSIONS LAAC with Amplatzer devices combined with structural, coronary, and electrophysiological procedures offers procedural feasibility and safety, as well as long-term efficacy.

Background We investigated the impact of an elevated plasma volume status (PVS) in patients undergoing TAVI on early clinical safety and mortality and assessed the prognostic utility of PVS for outcome prediction. Materials and methods We retrospectively calculated the PVS in 652 patients undergoing TAVI between 2009 and 2018 at two centres. They were then categorized into two groups depending on their preoperative PVS (PVS ≤−4; n = 257 vs PVS>−4; n = 379). Relative PVS was derived by subtracting calculated ideal (iPVS = c × weight) from actual plasma volume (aPVS = (1 − haematocrit) × (a + (b × weight in kg)). Results The need for renal replacement therapy (1 (0.4%) vs 17 (4.5%); P = .001), re‐operation for noncardiac reasons (9 (3.5%) vs 32 (8.4%); P = .003), re‐operation for bleeding (9 (3.5%) vs 27 (7.1%); P = .037) and major bleeding (14 (5.4%) vs 37 (9.8%); P = .033) were significantly higher in patients with a PVS>−4. The composite 30‐day early safety endpoint (234 (91.1%) vs 314 (82.8%); P = .002) confirms that an increased preoperative PVS is associated with a worse overall outcome after TAVI. Conclusions An elevated PVS (>−4) as a marker for congestion is associated with significantly worse outcome after TAVI and therefore should be incorporated in preprocedural risk stratification.

BACKGROUND The incidence of venous thromboembolism (VTE) and use of anticoagulation are rising in children, but treatment options remain limited. As a newer anticoagulant, fondaparinux may be a safe and effective alternative with the benefit of once-daily dosing, but there is relatively little data supporting its use. PROCEDURE This retrospective cohort study describes the long-term dosing, efficacy, and safety of fondaparinux for treatment of VTE in children at a single institution. The study included children

Thrombocytopenia after transcatheter aortic valve implantation (TAVI) is common and has been related to higher mortality and major complications. No comparison between balloon-expandable (BEV) and self-expanding valves (SEV) regarding drop platelet count (DPC) has been reported to date. The objectives of this study were to analyze the differences in DPC between BEVs or SEVs and their prognostic implications in clinical outcomes.We retrospectively analyzed patients undergoing TAVI. Platelet counts after TAVI were collected. Two groups were created: DPC ≤ 30% and DPC 30%. VARC-2 criteria were used to define outcomes.Study population was composed of 195 patients (age 77.5 ± 6.7, 57.4% males). All of them but one experienced DPC (mean DPC 31.9 ± 15.3%). DPC was significantly higher among the patients treated with BEV compared to those treated with SEV (36.3 ± 15.1% vs 27.7 ± 14.4, P 0.001). After multivariate analysis, the use of BEV was independently associated with a higher rate of DPC 30% (67.4% vs 36.0%; OR 3.4; 95% CI, 1.42-8.16). At 30 days, the DPC 30% was associated with a higher rate of life-threatening/major bleeding, major vascular complications, in-hospital sepsis and mortality. At one year, there were no statistically significant differences in the mortality rate between groups (6.35% vs 10.0%, HR 1.54; 95% CI, 0.56-4.25).In this study, the use of BEV was associated with a higher risk of DPC after TAVI. A DPC rate 30% was associated with an increased risk of major complications at 30 days.