Safety of outpatient management of cancer-associated pulmonary embolism: a retrospective study.

Not available.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Previous Ischemic Stroke Significantly Alters Stroke Risk in Newly Diagnosed Cancer Patients.

BACKGROUND: Previous ischemic stroke (IS) is a risk factor for subsequent IS in the general population; it is unclear if this relationship remains true in patients with cancer. Our objective was to examine the association between previous IS and risk for future IS in individuals newly diagnosed with cancer. METHODS: We conducted a retrospective population-based matched cohort study of newly diagnosed adult cancer patients (excluding nonmelanoma skin cancers and primary central nervous system tumors) in Ontario, Canada from 2010 to 2020; those with prior IS were matched (1:4) by age, sex, year of cancer diagnosis, cancer stage, and cancer site to those without a history of stroke. Cumulative incidence function curves were created to estimate the incidence of IS. Subdistribution adjusted hazard ratios (aHRs) and 95% CIs were calculated, where death was treated as a competing event. Multivariable analysis was adjusted for imbalanced baseline characteristics. RESULTS: We examined 65 525 individuals with cancer, including 13 070 with a history of IS. The median follow-up duration was 743 days (interquartile range, 177-1729 days). The incidence of IS following cancer diagnosis was 261.3/10 000 person-years in the cohort with prior IS and 75.3/10 000 person-years in those without prior IS. Individuals with prior IS had an increased risk for IS after cancer diagnosis compared with those without a history (aHR, 2.68 [95% CI, 2.41-2.98]); they also had more prevalent cardiovascular risk factors. The highest risk for stroke compared with those without a history of IS was observed in the gynecologic cancer (aHR, 3.84 [95% CI, 2.15-6.85]) and lung cancer (aHR, 3.18 [95% CI, 2.52-4.02]) subgroups. The risk of IS was inversely correlated with lag time of previous stroke; those with IS 1 year before their cancer diagnosis had the highest risk (aHR, 3.68 [95% CI, 3.22-4.22]). CONCLUSIONS: Among individuals with newly diagnosed cancer, those with IS history were almost 3× more likely to experience a stroke after cancer diagnosis, especially if the prediagnosis stroke occurred within 1 year preceding cancer diagnosis.

Urgent procedures or surgeries in patients receiving oral anticoagulants: a systematic literature review.

There are limited data about the frequency of urgent surgical emergencies among patients receiving oral anticoagulants (OACs). We conducted a systematic literature review of Medline and EMBASE for published English-language articles of adult patients receiving oral anticoagulant treatment (vitamin K antagonists, apixaban, dabigatran, edoxaban, rivaroxaban) that reported on patients experiencing unplanned emergent or urgent surgery/procedure or trauma. Randomized trials, observational studies, and case series (50-100 cases) were included. The primary outcome was the frequency of unplanned urgent surgery or invasive procedures among OAC-treated patients with a focus on those not precipitated by the presence of major bleeding. The protocol was not registered. Funding was provided by Covis Pharmaceuticals. The search yielded 1367 potential studies of which 34 were included in the final review. One study reported the rate of urgent surgery/procedures among a large cohort of patients treated with dabigatran or warfarin for atrial fibrillation (~ 1% per year). Another study reported the rate of bleeding or urgent surgery among OAC-treated patients experiencing a fracture or trauma (0.489% per patient-year). The remaining 32 studies were cohorts of OAC-treated patients who received reversal or hemostatic therapies for major bleeding or urgent surgery. A median of 28.8% of these patients underwent surgery or invasive procedure. Urgent surgery appears to be a common, yet understudied complication during OAC treatment potentially associated with high rates of adverse outcomes. With increased eligibility for OACs, future studies evaluating the management and outcomes in this setting are needed.

Small-volume tubes to reduce anemia and transfusion (STRATUS): a pilot study.

PURPOSE: Blood sampling for diagnostic testing causes blood loss. Small-volume tubes have the same cost, dimensions, and blood-draw techniques as standard-volume tubes, and are compatible with laboratory equipment; however, they are not commonly used. We sought to assess the feasibility of a stepped-wedge cluster trial to determine whether small-volume tubes reduce transfusion compared with standard-volume tubes in intensive care unit (ICU) patients. METHODS: We conducted a prospective mixed-methods pilot study (before-after design) in one ICU with a six-week control period (standard-volume tubes) and a six-week intervention period (small-volume tubes). All patients admitted to the ICU were included. Feasibility was assessed as successful switch to small-volume tubes; adherence to tube size; sufficient volume for testing; user acceptance; barriers and facilitators to implementation; and 95% transfusion collection. We explored end-user acceptability using focus groups. RESULTS: One hundred and sixty-five patients were included in the standard-volume and 204 in the small-volume periods. Transition to small-volume tubes was successful. Random audits showed 100% compliance. The proportion of samples with inadequate volume for testing was the same for both groups (both, 0.2%). Based on ten focus groups, small-volume tubes were acceptable with no barriers identified. Transfusion data collection was 100%. Median [interquartile range] estimated blood loss due to laboratory testing per patient per day in ICU was 11 [8-17] mL with standard-volume and 6 [4-8] mL with small-volume tubes. CONCLUSION: Small-volume tubes can be implemented with acceptability to end-users and without barriers. They did not result in an increased frequency of inadequate samples. These results inform a trial to determine whether small-volume tubes reduce transfusion. STUDY REGISTRATION: ClinicalTrials.gov (NCT03284944); registered 15 September 2017.

RéSUMé: OBJECTIF: Les prélèvements sanguins pour les tests diagnostiques provoquent des pertes de sang. Les tubes de prélèvement de petit volume entraînent le même coût, ont les mêmes dimensions et nécessitent les mêmes techniques de prélèvement sanguin que les tubes de volume standard, en plus d'être compatibles avec l'équipement de laboratoire; cependant, ils ne sont pas couramment utilisés. Nous avons cherché à évaluer la faisabilité d'un essai clinique à intervention échelonnée visant à déterminer si les tubes de petit volume réduisaient la transfusion par rapport aux tubes de volume standard chez les patient·es de l'unité de soins intensifs (USI). MéTHODE: Nous avons mené une étude pilote prospective à méthodes mixtes (conception avant-après) dans une unité de soins intensifs, avec une période de contrôle de six semaines (tubes de volume standard) et une période d'intervention de six semaines (tubes de petit volume). Tou·tes les patient·es admis·es à l'USI ont été inclus·es. La faisabilité a été évaluée comme étant la transition réussie vers des tubes de petit volume; le respect de la taille du tube; un volume suffisant pour les tests sanguins; l'acceptation de l'utilisateur·trice; les obstacles et les facilitateurs à la mise en œuvre; et une collecte de données de transfusion de 95 %. Nous avons exploré l'acceptabilité par l'utilisateur·trice final·e à l'aide de groupes de discussion. RéSULTATS: Cent soixante-cinq patient·es ont été inclus·es dans le groupe volume standard et 204 dans les groupes pour la période de petit volume. La transition vers des tubes de petit volume a été couronnée de succès. Les audits aléatoires ont montré une observance de 100 %. La proportion d'échantillons dont le volume était insuffisant pour l'analyse était la même dans les deux groupes (0,2 % dans les deux cas). D'après dix groupes de discussion, les tubes de faible volume étaient acceptables et aucun obstacle n'a été identifié. La collecte de données transfusionnelles était de 100 %. Les pertes de sang médianes estimées [écart interquartile] dues aux tests de laboratoire par patient·e et par jour à l'USI étaient de 11 [8 à 17] mL avec un volume standard et de 6 [4 à 8] mL avec des tubes de petit volume. CONCLUSION: Les tubes de petit volume peuvent être mis en œuvre en étant acceptés par les utilisateur·trices et sans obstacles. Ils n'ont pas entraîné une augmentation de la fréquence des échantillons inadéquats. Ces résultats procurent des informations pour une étude visant à déterminer si les tubes de petit volume réduisent la transfusion. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT03284944); enregistré le 15 septembre 2017.

Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial.

Importance: Blood collection for laboratory testing in intensive care unit (ICU) patients is a modifiable contributor to anemia and red blood cell (RBC) transfusion. Most blood withdrawn is not required for analysis and is discarded. Objective: To determine whether transitioning from standard-volume to small-volume vacuum tubes for blood collection in ICUs reduces RBC transfusion without compromising laboratory testing procedures. Design, Setting, and Participants: Stepped-wedge cluster randomized trial in 25 adult medical-surgical ICUs in Canada (February 5, 2019 to January 21, 2021). Interventions: ICUs were randomized to transition from standard-volume (n = 10 940) to small-volume tubes (n = 10 261) for laboratory testing. Main Outcomes and Measures: The primary outcome was RBC transfusion (units per patient per ICU stay). Secondary outcomes were patients receiving at least 1 RBC transfusion, hemoglobin decrease during ICU stay (adjusted for RBC transfusion), specimens with insufficient volume for testing, length of stay in the ICU and hospital, and mortality in the ICU and hospital. The primary analysis included patients admitted for 48 hours or more, excluding those admitted during a 5.5-month COVID-19-related trial hiatus. Results: In the primary analysis of 21 201 patients (mean age, 63.5 years; 39.9% female), which excluded 6210 patients admitted during the early COVID-19 pandemic, there was no significant difference in RBC units per patient per ICU stay (relative risk [RR], 0.91 [95% CI, 0.79 to 1.05]; P = .19; absolute reduction of 7.24 RBC units/100 patients per ICU stay [95% CI, -3.28 to 19.44]). In a prespecified secondary analysis (n = 27 411 patients), RBC units per patient per ICU stay decreased after transition from standard-volume to small-volume tubes (RR, 0.88 [95% CI, 0.77 to 1.00]; P = .04; absolute reduction of 9.84 RBC units/100 patients per ICU stay [95% CI, 0.24 to 20.76]). Median decrease in transfusion-adjusted hemoglobin was not statistically different in the primary population (mean difference, 0.10 g/dL [95% CI, -0.04 to 0.23]) and lower in the secondary population (mean difference, 0.17 g/dL [95% CI, 0.05 to 0.29]). Specimens with insufficient quantity for analysis were rare (≤0.03%) before and after transition. Conclusions and Relevance: Use of small-volume blood collection tubes in the ICU may decrease RBC transfusions without affecting laboratory analysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03578419.

Efficacy and Safety of Low Molecular Weight Heparin Versus Unfractionated Heparin for Prevention of Venous Thromboembolism in Trauma Patients: A Systematic Review and Meta-analysis.

PURPOSE: Trauma patients are at high risk of VTE. We summarize the efficacy and safety of LMWH versus UFH for the prevention of VTE in trauma patients. METHODS: We searched 6 databases from inception through March 12, 2021. We included randomized controlled trials (RCTs) or observational studies comparing LMWH versus UFH for thromboprophylaxis in adult trauma patients. We pooled effect estimates across RCTs and observational studies separately, using random-effects model and inverse variance weighting. We assessed risk of bias using the Cochrane tool for RCTs and the Risk of Bias in Non-Randomized Studies (ROBINS)-I tool for observational studies and assessed certainty of findings using Grading of Recommendations, Assessment, Development and Evaluations methodology. RESULTS: We included 4 RCTs (879 patients) and 8 observational studies (306,747 patients). Based on pooled RCT data, compared to UFH, LMWH reduces deep vein thrombosis (RR 0.67, 95% CI 0.50 to 0.88, moderate certainty) and VTE (RR 0.68, 95% CI 0.51 to 0.90, moderate certainty). As compared to UFH, LMWH may reduce pulmonary embolism [adjusted odds ratio from pooled observational studies 0.56 (95% CI 0.50 to 0.62)] and mortality (adjusted odds ratio from pooled observational studies 0.54, 95% CI 0.45 to 0.65), though based on low certainty evidence. There was an uncertain effect on adverse events (RR from pooled RCTs 0.80, 95% CI 0.48 to 1.33, very low certainty) and heparin induced thrombocytopenia [RR from pooled RCTs 0.26 (95% CI 0.03 to 2.38, very low certainty)]. CONCLUSIONS: Among adult trauma patients, LMWH is superior to UFH for deep vein thrombosis and VTE prevention and may additionally reduce pulmonary embolism and mortality. The impact on adverse events and heparin induced thrombocytopenia is uncertain.

Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Prognostic Factors Associated With Development of Venous Thromboembolism in Critically Ill Patients-A Systematic Review and Meta-Analysis.

OBJECTIVE: To identify prognostic factors for the development of venous thromboembolism in the ICU. DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception to March 1, 2021. STUDY SELECTION: We included English-language studies describing prognostic factors associated with the development of venous thromboembolism among critically ill patients. DATA EXTRACTION: Two authors performed data extraction and risk-of-bias assessment. We pooled adjusted odds ratios and adjusted hazard ratios for prognostic factors using random-effects model. We assessed risk of bias using the Quality in Prognosis Studies tool and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. DATA SYNTHESIS: We included 39 observational cohort studies involving 729,477 patients. Patient factors with high or moderate certainty of association with increased odds of venous thromboembolism include older age (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29 per 10 yr), obesity (adjusted odds ratio, 1.25; 95% CI, 1.18-1.32), active malignancy (adjusted odds ratio, 1.70; 95% CI, 1.18-2.44), history of venous thromboembolism (adjusted odds ratio, 4.77; 95% CI, 3.42-6.65), and history of recent surgery (adjusted odds ratio, 1.77; 95% CI, 1.26-2.47). ICU-specific factors with high or moderate certainty of association with increased risk of venous thromboembolism include sepsis (adjusted odds ratio, 1.41; 95% CI, 1.12-1.78), lack of pharmacologic venous thromboembolism prophylaxis (adjusted odds ratio, 1.80; 95% CI, 1.14-2.84), central venous catheter (adjusted odds ratio, 2.93; 95% CI, 1.98-4.34), invasive mechanical ventilation (adjusted odds ratio, 1.74; 95% CI, 1.36-2.24), and use of vasoactive medication (adjusted odds ratio, 1.86; 95% CI, 1.23-2.81). CONCLUSIONS: This meta-analysis provides quantitative summaries of the association between patient-specific and ICU-related prognostic factors and the risk of venous thromboembolism in the ICU. These findings provide the foundation for the development of a venous thromboembolism risk stratification tool for critically ill patients.

Rates of rebleeding, thrombosis and mortality associated with resumption of anticoagulant therapy after anticoagulant-related bleeding.

BACKGROUND: Data on resuming oral anticoagulants (OACs) after bleeding are primarily from studies involving patients given warfarin, with few data on direct OACs (DOACs). We aimed to characterize prescribing patterns for OACs after OAC-related bleeding and compare the rates of bleeding, thrombosis and mortality in patients who resumed either type of OAC with those who did not. METHODS: We conducted a population-based cohort study of adults aged 66 years or older who were admitted to hospital for bleeding while receiving OACs from Apr. 1, 2012, to Mar. 31, 2017, using linked administrative health databases from Ontario. We used competing risk methods to calculate cause-specific adjusted hazard ratios (HRs) for thrombosis, bleeding and mortality with resumption of OACs adjusted as a time-varying covariate. We determined time to OAC resumption using the Kaplan-Meier method. RESULTS: We included 6793 patients with gastrointestinal (n = 4297, 63.3%), intracranial (n = 805, 11.9%) or other bleeding (n = 1691, 25.0%). At cohort entry, 3874 patients (57.0%) were prescribed warfarin and 2919 patients (43.0%) were prescribed a DOAC. The most common indication for OAC was atrial fibrillation (n = 5557, 81.8%), followed by venous thromboembolism (n = 1367, 20.1%). Oral anticoagulants were resumed in 4792 patients (70.5%) within 365 days of the index bleed. The median time to resumption was 46 (interquartile range 6-550) days. We found that resuming OAC was associated with reduced rates of thrombosis (adjusted HR 0.60, 95% confidence interval [CI] 0.50-0.72) and mortality (adjusted HR 0.54, 95% CI 0.48-0.60), and an increased rate of rebleeding (adjusted HR 1.88, 95% CI 1.64-2.17). INTERPRETATION: We found that resuming OAC is associated with a reduction in thrombosis and mortality but an increase in bleeding. Randomized controlled trials that evaluate the net benefit of strategies for resumption of OAC after a bleeding event are warranted.

Blood loss from laboratory testing, anemia, and red blood cell transfusion in the intensive care unit: a retrospective study.

BACKGROUND: Anemia is common in critically ill patients and associated with adverse outcomes. Phlebotomy associated with laboratory testing is a potentially modifiable contributor. This study aims to 1) characterize the blood volume taken for laboratory testing, and 2) explore the effect of blood loss on red blood cell (RBC) transfusion and anemia in adult intensive care unit (ICU) patients. METHODS: Using a transfusion research database, we retrospectively reviewed consecutively admitted patients to four medical-surgical ICUs in Hamilton, Ontario, Canada. The primary outcome was estimated blood loss for laboratory testing during ICU admission. Secondary outcomes were hemoglobin (Hb) of 90 g/L or less and RBC transfusion. RESULTS: Among the 7273 patients included, the median blood volume per patient taken for laboratory testing during their ICU stay was 213 mL (interquartile range [IQR], 133-382 mL). On ICU admission, median Hb was 97 g/L (IQR, 82-116 g/L). An Hb of 90 g/L or less occurred in 67.0% of patients during their ICU stay. Median Hb on ICU discharge adjusted for RBC transfusion was 84 g/L (IQR, 58-105 g/L). RBC transfusion was administered to 47.5% of patients, who received a median of 3 units (IQR, 2-7 units). Cumulative blood loss due to laboratory testing from Day 2 to Day 7 of ICU admission was independently associated with RBC transfusion (hazard ratio, 2.28 for each 150-mL increment; 95% confidence interval, 2.02-2.59). CONCLUSIONS: Blood loss for laboratory testing is substantial in ICU patients and significantly associated with RBC transfusion. Strategies to reduce blood loss from laboratory testing represents an area for further investigation.

Devices to Reduce the Volume of Blood Taken for Laboratory Testing in ICU Patients: A Systematic Review.

BACKGROUND: Intensive care unit (ICU) patients are at high risk of anemia, which is associated with adverse clinical outcomes and death. Blood sampling for diagnostic testing is a potentially modifiable contributor to anemia. METHODS: We conducted a systematic review by searching MEDLINE and EMBASE from inception to October 5, 2017, for studies reporting the volume of blood taken for laboratory testing using blood sampling conservation devices compared to standard care or another intervention in adult ICU patients. RESULTS: We identified 8 eligible studies (n = 1204 patients) that used 2 types of devices: arterial access devices (n = 5) and reduced-volume blood collection tubes (n = 3). All studies reported a reduction in the volume of blood taken for laboratory testing with devices compared to standard practice (range 19%-80%). The studies were judged to have serious risk of bias, and due to heterogeneity, pooling for meta-analysis was not considered appropriate. CONCLUSIONS: Devices used to reduce the volume of blood taken for laboratory testing in ICU patients appear to be effective, although study heterogeneity limited our ability to calculate pooled estimates of efficacy for each device. Further assessment of clinical outcomes may establish clinical benefit with minimal negative consequences for hospitals and laboratories to facilitate the use of small-volume tubes.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.

BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

Benefits and Risks of Antithrombotic Therapy in Essential Thrombocythemia: A Systematic Review.

BACKGROUND: Patients with essential thrombocythemia (ET) are at high risk for both thrombosis and hemorrhage. PURPOSE: To evaluate the risks and benefits of antithrombotic therapy in adults with ET. DATA SOURCES: Multiple databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, through 4 March 2017. STUDY SELECTION: Randomized and observational studies of antiplatelet or anticoagulant therapy, published in any language and reporting thrombotic or hemorrhagic events. DATA EXTRACTION: Two reviewers independently extracted data, assessed risk of bias, and graded certainty of evidence. DATA SYNTHESIS: No relevant randomized trials were identified. Twenty-four observational studies (18 comparative and 6 single-group) involving 6153 patients followed for 31 711 patient-years were reviewed; most were deemed to have high risk of bias. Most patients receiving antiplatelet therapy (3613 of 4527 [80%]) received low-dose aspirin (50 to 150 mg/d); 914 (20%) received high-dose aspirin (300 to 600 mg/d), dipyridamole, or other agents. Overall, findings were inconsistent and imprecise. The reported incidence rates of thrombosis, any bleeding, and major bleeding without antiplatelet therapy ranged from 5 to 110 (median, 20), from 3 to 39 (median, 8), and from 2 to 53 (median, 6) cases per 1000 patient-years, respectively. The reported relative risks for thrombosis, any bleeding, and major bleeding with antiplatelet therapy compared with none ranged from 0.26 to 3.48 (median, 0.74), from 0.48 to 11.04 (median, 1.95), and from 0.48 to 5.17 (median, 1.30), respectively. Certainty of evidence was rated low or very low for all outcomes. LIMITATION: No randomized trials, no extractable data on anticoagulants, lack of uniform bleeding definitions, and systematic reporting of outcomes. CONCLUSION: Available evidence about the risk-benefit ratio of antiplatelet therapy in adults with ET is highly uncertain. PRIMARY FUNDING SOURCE: Regional Medical Associates. (PROSPERO: CRD42015027051).

How I treat target-specific oral anticoagulant-associated bleeding.

Target-specific oral anticoagulants (TSOACs) that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are effective and safe alternatives to vitamin K antagonists (VKAs) and low-molecular-weight heparin (LMWH). Although these agents have practical advantages compared with VKAs and LMWH, there are no antidotes that reverse their anticoagulant effect. Clinical evidence for the efficacy of nonspecific therapies that promote formation of fibrin (prothrombin complex concentrate [PCC], activated PCC [aPCC], and recombinant factor VIIa) in the setting of TSOAC-associated bleeding is lacking, and these prohemostatic products are associated with a risk of thrombosis. In the absence of specific antidotes, addition of PCC or aPCC to maximum supportive therapy may be reasonable for patients with severe or life-threatening TSOAC-associated bleeding. Targeted antidotes for these agents are in development.