Platelet-activating functional assay resolution in vaccine-induced immune thrombotic thrombocytopenia: differential alignment to PF4 ELISA platforms.

Background: Anti-platelet factor 4 (PF4) antibodies in vaccine-induced immune thrombotic thrombocytopenia (VITT) appear to be transient, with discrepant persistence depending on the platform used for detection. Objectives: We aimed to report a longitudinal study of antibody persistence using 2 ELISA platforms and 2 platelet-activating functional assays in a clinical cohort of patients with VITT referred for follow-up testing. Methods: In total, 32 Australian patients with VITT or pre-VITT, confirmed by expert adjudication, with samples referred for clinical follow-up were included. Clinical follow-up assays, including Stago and Hyphen ELISAs, procoagulant platelet flow cytometry, and modified PF4-serotonin-release assay, were performed according to the pattern of reactivity for that patient at diagnosis. Results: The median follow-up was 24 weeks after diagnosis. A general decline in anti-PF4 antibody levels and platelet-activating capacity over time was observed with a more rapid median time to resolution of 16 weeks by functional assay vs 24 weeks by Stago ELISA. Decline in platelet-activating antibody levels detected by functional assays mirrored Stago ELISA titer but not Hyphen. However, 87% of patients received a documented second vaccination and 74% received an mRNA booster with no reported adverse events. Conclusion: Anti-PF4 antibodies persist longer than functional platelet-activating antibodies in VITT but do not warrant avoidance of subsequent vaccinations. Persistence detection is assay-dependent. Stago ELISA may be a surrogate where functional assays are unavailable for follow-up testing of confirmed patients with VITT.

Serotonin Release Assay: Functional Assay for Heparin- and Vaccine-Induced (Immune) Thrombotic Thrombocytopenia.

The serotonin release assay (SRA) has been the gold-standard assay for detection of heparin-dependent platelet-activating antibodies and integral for the diagnosis for heparin-induced thrombotic thrombocytopenia (HIT). In 2021, a thrombotic thrombocytopenic syndrome was reported after adenoviral vector COVID-19 vaccination. This vaccine-induced thrombotic thrombocytopenic syndrome (VITT) proved to be a severe immune platelet activation syndrome manifested by unusual thrombosis, thrombocytopenia, very elevated plasma D-dimer, and a high mortality even with aggressive therapy (anticoagulation and plasma exchange). While the platelet-activating antibodies in both HIT and VITT are directed toward platelet factor 4 (PF4), important differences have been found. These differences have required modifications to the SRA to improve detection of functional VITT antibodies. Functional platelet activation assays remain essential in the diagnostic workup of HIT and VITT. Here we detail the application of SRA for the assessment of HIT and VITT antibodies.

Long-Term Risk of Major Bleeding after Discontinuing Anticoagulation for Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. OBJECTIVES: To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. RESULTS: Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n = 41) and fatal bleeding (n = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20-0.54) and 0.09 (95% CI: 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6-31.1%). CONCLUSION: The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis.

OBJECTIVES: To determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence for recurrent VTE up to 10 years. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019). STUDY SELECTION: Randomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment. DATA EXTRACTION AND SYNTHESIS: Two investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity. RESULTS: 18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%). CONCLUSIONS: In patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017056309.

Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Siltuximab in High-Risk Smoldering Multiple Myeloma.

PURPOSE: IL6 is important for the growth and survival of myeloma cells. This study evaluated blocking IL6 with siltuximab to delay the transition from high-risk smoldering multiple myeloma (SMM) to multiple myeloma. PATIENTS AND METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 85 patients with high-risk SMM were randomized to 15 mg/kg siltuximab (43 patients) or placebo (42 patients). The primary endpoint was 1-year progression-free survival (PFS) rate, based on IMWG CRAB criteria. Secondary endpoints included progressive disease indicator rate, PFS, and safety. RESULTS: Median age was 62 years (range: 21-84); 57% were male and 87% had a baseline Eastern Cooperative Oncology Group score of 0. The 1-year PFS rate was 84.5% (siltuximab) and 74.4% (placebo). After a median follow-up of 29.2 months, 32.6% of PFS events occurred with siltuximab and 42.9% with placebo. Median PFS was not reached with siltuximab but was 23.5 months with placebo [HR 0.50 (95% confidence interval, 0.24-1.04); P = 0.0597]. The safety profile of siltuximab was comparable with placebo. Most adverse events in the siltuximab group were grade 2/3; the most common serious adverse events were infections/infestations, and renal/urinary disorders. Mortality was low in both groups (3 deaths in the siltuximab group and 4 in the placebo group). CONCLUSIONS: Although this study did not meet the prespecified protocol hypothesis criteria, data suggest that siltuximab may delay the progression of high-risk SMM.

Risk of recurrent venous thromboembolism according to baseline risk factor profiles.

The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy.

Long-term risk of recurrence after discontinuing anticoagulants for a first unprovoked venous thromboembolism: protocol for a systematic review and meta-analysis.

INTRODUCTION: For patients with a first unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is a crucial clinical dilemma which has yet to be resolved. The decision to stop anticoagulant therapy (AT) after the initial 3-6 months or to continue AT indefinitely, is primarily governed by the long-term risk of recurrence when treatment is discontinued. This risk however, is not well established, hindering decision making. METHODS AND ANALYSIS: We will conduct a systematic review and a meta-analysis of studies involving patients diagnosed with a first, symptomatic unprovoked VTE or VTE provoked by minor transient risk factors, who have completed at least 3 months of initial AT; and who were followed-up for standardised time intervals of 1, 2, 5, 10 and 20 years (±3 months) after stopping AT. We will search (from inception to January 2017) MEDLINE, Embase and the Cochrane library for randomised controlled trials and prospective observational studies. Two reviewers will conduct all screening and data collection independently. The primary outcome of the rate of recurrent VTE at the standardised time intervals will be calculated for each study from the total number of recurrent events and the corresponding number of patient-years of follow-up. We will use a random-effects model to pool study results and report a weighted estimate of the absolute rate of recurrent VTE (events per 100 patient-years) over standardised time intervals of 1, 2, 5, 10 and 20 years after discontinuing anticoagulants. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study. Findings from this study will be disseminated through peer-reviewed journal publication as well as relevant national and international conference presentations. PROSPERO REGISTRATION NUMBER: CRD42017056309.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism.

BACKGROUND: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. METHODS: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTS: A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONS: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).

Long-term Anticoagulation With Rivaroxaban for Preventing Recurrent VTE: A Benefit-Risk Analysis of EINSTEIN-Extension.

BACKGROUND: Short-term anticoagulant treatment for acute DVT or pulmonary embolism (PE) effectively reduces the risk of recurrent disease during the first 6 to 12 months of therapy. Continued anticoagulation often is not instituted because of the perception among physicians that the risk of major bleeding will outweigh the risk of new venous thrombotic episodes. METHODS: The authors performed a benefit-risk analysis by using the randomized EINSTEIN-Extension trial, which compared continued rivaroxaban with placebo in 1,197 patients with symptomatic DVT or PE who had completed 6 to 12 months of anticoagulation and in whom physicians had equipoise with respect to the need for continued anticoagulation. One-year Kaplan-Meier rates and rate differences of recurrent VTE and major bleeding were calculated. Benefits and risks were assessed using rate differences scaled to a population size of 10,000 patients treated for 1 year. RESULTS: Recurrent VTE occurred in eight recipients of rivaroxaban and 42 patients receiving placebo. In a population of 10,000 patients treated for 1 year, rivaroxaban treatment would have resulted in 665 (95% CI, 246-1,084) fewer recurrent VTEs than would placebo (number needed to treat = 15). Major bleeding occurred in four (0.7%) and zero patients, respectively. Rivaroxaban treatment would have resulted in 68 (95% CI, 2-134) more major bleeding events than would placebo (number needed to harm = 147). Kaplan-Meier analysis showed early recurrent VTE reduction with rivaroxaban that continued to improve throughout treatment; major bleeding increased gradually, plateauing at approximately 100 days. CONCLUSIONS: A clinically important benefit and a favorable benefit-risk profile of continued rivaroxaban anticoagulation was observed. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00439725; URL: www.clinicaltrials.gov.

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration.

Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1.

Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development.

Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study.

Patients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6-12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).

Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration.

BACKGROUND: In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups. METHODS AND RESULTS: An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months' median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47-0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41-1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50-0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40-0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients. CONCLUSIONS: Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding. CLINICAL TRIAL REGISTRATION URL: www.anzctr.org.au. Unique identifier: ACTRN12611000684921.

Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin.

IMPORTANCE: Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented. OBJECTIVE: To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism. DESIGN, SETTING, AND PARTICIPANTS: Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009. EXPOSURE: Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure. MAIN OUTCOMES AND MEASURES: Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios. RESULTS: During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens. CONCLUSIONS AND RELEVANCE: Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding.

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies.

BACKGROUND: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. METHODS: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. RESULTS: A total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority < 0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p = 0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy. CONCLUSION: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups. TRIAL REGISTRATION EINSTEIN-PE: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.

Low-dose aspirin for preventing recurrent venous thromboembolism.

BACKGROUND: Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism. METHODS: We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism. RESULTS: During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events. CONCLUSIONS: In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662.).

Validation of whole blood impedance aggregometry as a new diagnostic tool for HIT: results of a large Australian study.

Heparin-induced thrombocytopenia (HIT) remains a challenge, with diagnosis confirmed only by functional assays. The gold standard 14C-serotonin release assay (SRA) is highly sensitive but technically challenging and unsuitable for routine use. We conducted a large study to validate whole blood impedance aggregometry (WBIA) as a suitable diagnostic tool for HIT. WBIA and SRA were used to test 181 samples positive for H-PF4 antibodies by PaGIA or ELISA. Using the same high responder donor, 77 samples were positive by WBIA (aggregation with low-dose but not high-dose heparin). Using the strict definition for SRA positivity, 72 samples were true HIT. In nine samples, serotonin release with high-dose heparin dropped by > 50% but was still >20%; these were retested after a one-half dilution and 8/9 became positive. Ten other samples were discrepant between the two assays: one strongly positive (89% release) and six weakly positive samples by SRA (average release 56%) were WBIA negative. When these samples were retested using a random donor, only two remained SRA positive. Three samples were strongly WBIA positive but SRA negative; two were retested by SRA with 0.5IU/ml heparin and one became positive. Under controlled conditions, using the same selected high-responder donor, WBIA and SRA performed similarly with slightly increased sensitivity of the WBIA when using the strict definition of SRA positivity. WBIA is easy to perform with rapid turn-around time and warrants a multi-laboratory trial to complete its validation as a confirmatory assay for platelet-activating HIT antibodies.

The direct factor Xa inhibitor rivaroxaban.

Warfarin and heparin are the traditional mainstay anticoagulant therapies for treating thromboembolic disease. These drugs, with a documented history of utility, also have inherent difficulties in usage; in particular, the complicated monitoring and numerous drug-drug interactions of warfarin, and the need for parenteral administration of heparins. New agents have recently emerged that target specific elements of the clotting pathway. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5-9 hours). Evidence from recently published large-scale phase III clinical trials shows rivaroxaban to be superior to enoxaparin for prophylaxis of venous thromboembolism after major orthopaedic surgery. Studies have shown rivaroxaban to have a sound safety profile, with an incidence of bleeding similar to enoxaparin in phase III clinical trials. Few side effects and drug-drug interactions between rivaroxaban and common medications have been found thus far, although some interactions with potent cytochrome P450 3A4 inhibitors have been observed. It is hoped that rivaroxaban may be used as a first-line anticoagulant for prophylaxis of venous thromboembolic disease in postsurgical patients.

Platelet function testing in uraemic patients.

INTRODUCTION: Chronic renal failure (CRF) is associated with excessive bleeding for a variety of reasons. Platelet dysfunction is probably the most consistent and important feature, particularly platelet-platelet and platelet-vessel wall interactions. The skin bleeding time (SBT) is the best established predictor of bleeding in uraemic patients but suffers from poor reproducibility and accuracy. Several newer rapid assays of platelet function are able to provide a means of assessing primary haemostasis, but have not been specifically assessed in uraemic patients. METHODS: A single centre, prospective cohort study of patients referred to a tertiary nephrology unit. Patients with both acute and chronic renal impairment were recruited. Laboratory parameters analysed included full blood count, serum creatinine and urea, calculated glomerular filtration rate (GFR) (Cockcroft formulae) APTT PT fibrinogen, SBT, whole blood platelet aggregation (WBPA), platelet function analyzer (PFA-100), thromboelastograph (TEG) and cone platelet analyzer (CPA). RESULTS: This study included 42 patients: nine with CRF (GFR < 30 ml/min) who were not receiving dialysis; 23 with CRF receiving dialysis; seven who presented in acute renal failure; and three assessed with normal renal function but with nephrotic syndrome and who presented prior to renal biopsy. Twenty-two patients were on low-dose aspirin and four patients were on clopidogrel. There was weak correlation between calculated GFR and SBT (r(2) = 0.1564) with even poorer correlation with serum creatinine and no correlation with urea levels. Overall, PFA-100 was a poor predictor of SBT. Seven of 12 patients with SBT <7 min had abnormal WBPA, 24 of 26 had abnormal WBPA if SBT >7 min. Of those with SBT <7 min, five had abnormal CPA, and >7 min, 15 of 21 had abnormal results. Nineteen patients had abnormal TEG tracings. Six patients underwent renal biopsies with one bleeding complication. CONCLUSIONS: In this pilot study we found that prolonged SBT was not predicted by serum creatinine or calculated GFR. Within the limitations of this study, an alternative in vitro test to replicate the SBT has not been identified.