The risk of hospitalisation from RSV is not increased by co-infection in children under 24-months-of-age.

The recent pandemic prompted renewed interest in paediatric respiratory infections, including whether co-infections - particularly with RSV - have an adverse prognostic impact. We evaluated the charts of all children presenting with respiratory symptoms to our unit between October 2022 and April 2023, each of whom was subjected to a multiplex PCR assay to detect eight viral targets and one bacterial target and examine the relationships between mono- and co-infections and hospitalization outcomes. We observed that younger age and RSV infection were both associated with the need for hospitalisation and the duration of hospitalisation after adjusting for confounders. Co-infection was, however, not associated with these outcomes.   Conclusion: This real-world data add to a growing consensus that RSV increases the risk of hospitalisation, while other co-infections, except for co-infection with SARS-CoV-2, do not. Given the timeframe over which our study was conducted, only a few children had SARS-CoV-2 co-infection, so we could not confirm any significant effect from this interaction. What is Known: • RSV increases the risk of hospitalisation and the need tor ventilatory support, especially in very young children. What is New: • Younger age and RSV infection were both associated with the need for hospitalisation and the duration of hospitalisation after adjusting for confounders. • Co-infection was, however, not associated with these outcomes.

Genomic epidemiology of the main SARS-CoV-2 variants in Italy between summer 2020 and winter 2021.

Since the beginning of the pandemic, SARS-CoV-2 has shown a great genomic variability, resulting in the continuous emergence of new variants that has made their global monitoring and study a priority. This work aimed to study the genomic heterogeneity, the temporal origin, the rate of viral evolution and the population dynamics of the main circulating variants (20E.EU1, Alpha and Delta) in Italy, in August 2020-January 2022 period. For phylogenetic analyses, three datasets were set up, each for a different main lineage/variant circulating in Italy in that time including other Italian and International sequences of the same lineage/variant, available in GISAID sampled in the same times. The international dataset showed 26 (23% Italians, 23% singleton, 54% mixed), 40 (60% mixed, 37.5% Italians, 1 singleton) and 42 (85.7% mixed, 9.5% singleton, 4.8% Italians) clusters with at least one Italian sequence, in 20E.EU1  clade, Alpha and Delta variants, respectively. The estimation of tMRCAs in the Italian clusters (including >70% of genomes from Italy) showed that in all the lineage/variant, the earliest clusters were the largest in size and the most persistent in time and frequently mixed. Isolates from the major Italian Islands tended to segregate in clusters more frequently than those from other part of Italy. The study of infection dynamics showed a positive correlation between the trend in the effective number of infections estimated by BSP model and the Re curves estimated by birth-death skyline plot. The present work highlighted different evolutionary dynamics of studied lineages with high concordance between epidemiological parameters estimation and phylodynamic trends suggesting that the mechanism of replacement of the SARS-CoV-2 variants must be related to a complex of factors involving the transmissibility, as well as the implementation of control measures, and the level of cross-immunization within the population.

Acute Generalized Exanthematous Pustulosis (AGEP) in 12 Patients Treated for SARS-CoV-2 Positive Pneumonia.

ABSTRACT: The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading throughout the world. The study describes 12 patients with SARS-CoV-2 pneumonia, who developed an acute erythematous rash with nonfollicular pinhead-sized pustules, without mucosal involvement. The clinical differential diagnosis was viral rash, acute generalized exanthematous pustulosis (AGEP), or multiform erythema. computed tomography with a diagnosis of interstitial pneumonia and a respiratory tract sample positive for SARS-CoV-2 in a reverse transcriptase polymerase chain reaction assay. Patients had signs of respiratory distress and were treated with hydroxychloroquine, darunavir, ritonavir, heparin, ceftriaxone, and azithromycin. Punch biopsies showed subcorneal pustules typical of AGEP. Dermal microvascular injury and thrombosis as described in skin damage by SARS-CoV-2 infection was not observed. The direct immunofluorescence for IgG, IgA, IgM, and C3 was negative in 8 patients investigated. A polymerase chain reaction for RNA SARS-CoV-2 performed on frozen skin was negative in 5 of 6 patients. Most of our patients were treated with systemic corticosteroids. After some days (4-10), the diffuse erythema and pustules had improved. AGEP is classified as a severe cutaneous adverse reaction, provoked by drugs and acute infections. Characteristically, removal of the offending agent leads to spontaneous resolution typically in less than 15 days. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. Cutaneous adverse reactions to drugs are common and are major health problems worldwide causing considerable costs for health care systems. We suggest that in the patients with AGEP during SARS-CoV-2 pneumonia, viral infection is a risk factor for developing drug reaction.

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones (p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.

Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-ß2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring.

COVID-19 is an infection induced by the SARS-CoV-2 coronavirus, and severe forms can lead to acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) management. Severe forms are associated with coagulation changes, mainly characterized by an increase in D-dimer and fibrinogen levels, with a higher risk of thrombosis, particularly pulmonary embolism. The impact of obesity in severe COVID-19 has also been highlighted.In this context, standard doses of low molecular weight heparin (LMWH) may be inadequate in ICU patients, with obesity, major inflammation, and hypercoagulability. We therefore urgently developed proposals on the prevention of thromboembolism and monitoring of hemostasis in hospitalized patients with COVID-19.Four levels of thromboembolic risk were defined according to the severity of COVID-19 reflected by oxygen requirement and treatment, the body mass index, and other risk factors. Monitoring of hemostasis (including fibrinogen and D-dimer levels) every 48 h is proposed. Standard doses of LMWH (e.g., enoxaparin 4000 IU/24 h SC) are proposed in case of intermediate thrombotic risk (BMI < 30 kg/m2, no other risk factors and no ARDS). In all obese patients (high thrombotic risk), adjusted prophylaxis with intermediate doses of LMWH (e.g., enoxaparin 4000 IU/12 h SC or 6000 IU/12 h SC if weight > 120 kg), or unfractionated heparin (UFH) if renal insufficiency (200 IU/kg/24 h, IV), is proposed. The thrombotic risk was defined as very high in obese patients with ARDS and added risk factors for thromboembolism, and also in case of extracorporeal membrane oxygenation (ECMO), unexplained catheter thrombosis, dialysis filter thrombosis, or marked inflammatory syndrome and/or hypercoagulability (e.g., fibrinogen > 8 g/l and/or D-dimers > 3 µg/ml). In ICU patients, it is sometimes difficult to confirm a diagnosis of thrombosis, and curative anticoagulant treatment may also be discussed on a probabilistic basis. In all these situations, therapeutic doses of LMWH, or UFH in case of renal insufficiency with monitoring of anti-Xa activity, are proposed.In conclusion, intensification of heparin treatment should be considered in the context of COVID-19 on the basis of clinical and biological criteria of severity, especially in severely ill ventilated patients, for whom the diagnosis of pulmonary embolism cannot be easily confirmed.

Recurrent Bleedings in Newborn: A Factor VII Deficiency Case Report.

Background: Major hemorrhages in newborns can be caused by several conditions, and knowledge of the differential diagnosis is essential in order to ensure prompt recognition and appropriate treatment. Case Report: We describe the case of a male newborn experiencing recurrent hemorrhages from the first days of life. Laboratory findings showed normal platelet count, hepatic function, and C-reactive protein. Coagulation tests detected an isolated prothrombin time (PT) prolongation and severe factor VII (FVII) deficiency. Conclusion: Inherited FVII deficiency is a rare autosomal recessive bleeding disorder. Clinical presentation is heterogeneous, and bleeding severity is not directly related to FVII levels. Acute bleeding episodes can be treated with human plasma-derived FVII (pdFVII) or recombinant activated FVII (rFVIIa). In case of severe deficiency, prophylaxis must be evaluated. Awareness of this condition is crucial in order to establish prompt diagnosis and treatment.

Duration of anticoagulation after isolated pulmonary embolism.

In the D-dimer and ULtrasonography in Combination Italian Study (DULCIS), serial D-dimer measurement in combination with assessment of residual thrombosis (in patients with deep vein thrombosis (DVT)) identified patients who safely discontinued anticoagulation after an unprovoked venous thromboembolism (VTE).In this subgroup analysis, the value of D-dimer tests was assessed in patients with isolated pulmonary embolism (PE) compared with those with DVT, with or without PE (DVT/PE). The DULCIS database was reanalysed in relation to this target.26.8% of the DULCIS patients had isolated PE as the index event; this was more prevalent in females (34.1%) than in males (21.1%; p<0.0001). The rate of positive D-dimer was similar in isolated PE and DVT/PE. The rate of recurrences was not different in isolated PE or DVT/PE patients (4.8% ppy versus 3.8% ppy; nonsignificant) who stopped anticoagulation for negative D-dimer, but it was markedly high (11.2% ppy; p<0.0001) in those with isolated PE who remained without anticoagulation despite positive D-dimer. Recurrences were more frequently new isolated PE in patients with isolated PE than with DVT/PE (six (46.2%) out of 13 versus two (7.4%) out of 27; p=0.0085).Serial D-dimer assessment can inform on the risk of recurrent VTE and help determine the duration of anticoagulation in patients with isolated PE.

D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study.

The optimal duration of anticoagulation in patients with venous thromboembolism (VTE) is uncertain. We investigated whether persistently negative D-dimers in patients with vein recanalization or stable thrombotic burden can identify subjects at low recurrence risk. Outpatients with a first VTE (unprovoked or associated with weak risk factors) were eligible after at least 3 months (12 in those with residual thrombosis) of anticoagulation. They received serial D-dimer measurements using commercial assays with predefined age/sex-specific cutoffs and were followed for up to 2 years. Of 1010 patients, anticoagulation was stopped in 528 (52.3%) with persistently negative D-dimer who subsequently experienced 25 recurrences (3.0% pt-y; 95% confidence interval [CI], 2.0-4.4%). Of the remaining 482 patients, 373 resumed anticoagulation and 109 refused it. Recurrent VTE developed in 15 patients (8.8% pt-y; 95% CI, 5.0-14.1) of the latter group and in 4 of the former (0.7% pt-y; 95% CI, 0.2-1.7; hazard ratio = 2.92; 95% CI, 1.87-9.72; P = .0006). Major bleeding occurred in 14 patients (2.3% pt-y; 95% CI, 1.3-3.9) who resumed anticoagulation. Serial D-dimer measurement is suitable in clinical practice for the identification of VTE patients in whom anticoagulation can be safely discontinued. This study was registered at clinicaltrials.gov as #NCT00954395.

How the direct oral anticoagulant apixaban affects hemostatic parameters. Results of a multicenter multiplatform study.

BACKGROUND: Apixaban is a newly developed direct oral anticoagulant targeting activated factor X (FXa). The degree of interference of apixaban with coagulation parameters has not been thoroughly investigated. METHODS: Increasing amounts of apixaban were added to aliquots of a pooled normal plasma (PNP) to mimic a large range of concentrations (n=8) that are observed in treated patients. Upon preparation, samples were stored frozen and tested for a vast array of coagulation parameters (including procoagulant and anticoagulant factors) in three laboratories, using three widely used coagulation platforms (reagent/coagulometer combinations). RESULTS: Results for each parameter were expressed as ratios of the value corresponding to each apixaban concentration to the value corresponding to the PNP without apixaban. By definition, ratios higher or lower than the unity define overestimation or underestimation, respectively. Prothrombin and activated partial thromboplastin times were barely prolonged by apixaban 200 ng/mL (ratios <1.29 or <1.19, respectively). Conversely, antithrombin was considerably overestimated when the measurement was made with FXa as target enzyme (ratios up to 1.43). Protein C and protein S were overestimated when measured as anticoagulant activities (ratios up to 1.20 or 1.95, respectively), and most measurements for individual coagulation factors (except fibrinogen) were considerably underestimated (ratios from 0.62 to 1.01). CONCLUSIONS: This large multicenter multiplatform study investigating a common set of test plasmas shows that apixaban interferes with the measurement of most coagulation parameters requested for investigation of hemostasis and highlights the need for a careful interpretation of results obtained in patients under treatment.

Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey.

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.

D-dimer testing for suspected venous thromboembolism in the emergency department. Consensus document of AcEMC, CISMEL, SIBioC, and SIMeL.

D-dimer testing is currently considered a cornerstone in the diagnostic approach of patients with suspected venous thromboembolism (VTE) across different health-care settings, including the emergency department (ED). Nevertheless, inappropriate or incorrect activities developing throughout the total testing process may substantially impair the clinical usefulness of this test and delay or even challenge the fast rule out or diagnosis of VTE. The leading problem of D-dimer is represented by the poor specificity for diagnosing VTE, wherein a minority of patients with a positive D-dimer are finally diagnosed with VTE, and even more importantly, the specificity further decreases with ageing, thus contributing to increase the overcrowding in short stay units such as the ED. Due to the large heterogeneity that characterizes the use of D-dimer in the emergency room, three Italian societies of laboratory medicine (Italian Committee for Standardization of Hematology and Laboratory Methods, Italian Society of Clinical Biochemistry and Molecular Biology, and Italian Society of Laboratory Medicine), along with the Academy of Emergency Medicine and Care, have developed a consensus document about the use of D-dimer testing for diagnostics of patients with suspected VTE in this health-care setting. The evidence-based indications contained in this document will cover the leading preanalytical, analytical, and postanalytical issues that may impair the clinical efficacy of D-dimer testing in the ED.

Practical Suggestions for an Optimal Management of Vitamin K Antagonists: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

In the era of direct oral anticoagulants, vitamin K antagonists retain a clinically relevant role in thrombotic disorders. In Italy, approximately 20% of the patients on anticoagulant therapies receives a VKA, in most cases warfarin. The optimal management of this drug is challenging and cannot disregard its intricate and unpredictable pharmacokinetic properties and patient's thrombotic and bleeding risk. Several clinical issues encountered during warfarin treatment are still unanswered and are tentatively addressed by physicians. In this regard, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) provides some experience-based good clinical practice's suggestions on the following topics: (1) how to start the anticoagulant treatment with warfarin and warfarin induction regimen; (2) how to manage a subtherapeutic INR value; (3) how to manage a supratherapeutic INR value in asymptomatic patients; and (4) how to manage the association of warfarin with interfering drugs.

Machine learning approach for prediction of outcomes in anticoagulated patients with atrial fibrillation.

BACKGROUND: The accuracy of available prediction tools for clinical outcomes in patients with atrial fibrillation (AF) remains modest. Machine Learning (ML) has been used to predict outcomes in the AF population, but not in a population entirely on anticoagulant therapy. METHODS AND AIMS: Different supervised ML models were applied to predict all-cause death, cardiovascular (CV) death, major bleeding and stroke in anticoagulated patients with AF, processing data from the multicenter START-2 Register. RESULTS: 11078 AF patients (male n = 6029, 54.3%) were enrolled with a median follow-up period of 1.5 years [IQR 1.0-2.6]. Patients on Vitamin K Antagonists (VKA) were 5135 (46.4%) and 5943 (53.6%) were on Direct Oral Anticoagulants (DOAC). Using Multi-Gate Mixture of Experts, a cross-validated AUC of 0.779 ± 0.016 and 0.745 ± 0.022 were obtained, respectively, for the prediction of all-cause death and CV-death in the overall population. The best ML model outperformed CHA2DSVA2SC and HAS-BLED for all-cause death prediction (p < 0.001 for both). When compared to HAS-BLED, Gradient Boosting improved major bleeding prediction in DOACs patients (0.711 vs. 0.586, p < 0.001). A very low number of events during follow-up (52) resulted in a suboptimal ischemic stroke prediction (best AUC of 0.606 ± 0.117 in overall population). Body mass index, age, renal function, platelet count and hemoglobin levels resulted the most important variables for ML prediction. CONCLUSIONS: In AF patients, ML models showed good discriminative ability to predict all-cause death, regardless of the type of anticoagulation strategy, and major bleeding on DOAC therapy, outperforming CHA2DS2VASC and the HAS-BLED scores for risk prediction in these populations.

D-dimer and risk of venous thromboembolism recurrence: Comparison of two studies with similar designs but different laboratory and clinical results.

BACKGROUND: D-dimer testing may help deciding the duration of anticoagulation in subjects at high risk of venous thromboembolism (VTE) recurrence. Two management studies on this issue have been published (DULCIS in 2014 and APIDULCIS in 2022). They had similar designs but had important different results. Aim of this article is to compare their results. METHODS: Both studies were finalized to extend anticoagulation [with vitamin K anticoagulants (VKAs) in DULCIS or apixaban 2.5 mg BID (kindly provided by BMS-Pfizer Collaboration) in APIDULCIS] only in patients with positive D-dimer results. RESULTS: More D-dimer assays resulted positive in APIDULCIS than in DULCIS (61.1 % vs 47.7 %, respectively; p < 0.0001). While only 4 (0.5 %) refused low dose apixaban in APIDULCIS, the 22.6 % of patients with positive D-dimer refused to resume VKAs in DULCIS; their rates of recurrence were 187 and 8.8 per 100 person-years, respectively (incidence rate ratio [IRR]: 21.2). The incidence of bleeding was low in those receiving apixaban vs those who resumed VKAs (0.4 vs 2.3 per 100 person-years, respectively; IRR 0.17;). While the recurrence rate was low and similar in the studies in subjects who resumed anticoagulation, it was significantly higher in APIDULCIS than in DULCIS in those who stopped anticoagulation for negative D-dimer (5.6 vs 3.0 per 100 person-years, respectively; IRR 1.9). CONCLUSION: The low dose Apixaban for extended VTE treatment is effective and safe, and well accepted by patients. Why subjects who stopped anticoagulation for negative D-dimer had a higher recurrence rate in APIDULCIS than in DULCIS remains to be explained.

Long-Term Outcomes in Two-Year Follow-Up after Primary Treatment in Patients with a Prior Venous Thromboembolic Event: A Prospective, Observational, Real-Life Study.

BACKGROUND: Patients with acute venous thromboembolism (VTE) need anticoagulation (AC) therapy for at least 3/6 months (primary treatment); after that period, they should receive a decision on the duration of therapy. METHODS: This study examined the complications occurring during two years of follow-up (FU) in patients with a first VTE who were recruited in 20 clinical centers and had discontinued or prolonged AC. They were included in the START2-POST-VTE prospective observational study. RESULTS: A total of 720 patients (53.5% males) who, after the completion of primary treatment, had received the decision to continue (n = 281, 39%; 76.1% with a DOAC) or discontinue (n = 439, 61%) AC were followed up for 2 years (total FU = 1318 years). The decision to prolong or suspend AC was made in similar proportions in patients with unprovoked or provoked index events. Courses of sulodexide treatment or Aspirin (100 mg daily) were prescribed to 20.3% and 4.5%, respectively, of the patients who discontinued AC. The bleeding rate was significantly higher in patients who extended AC (1.6% pt/y) than in those who stopped AC (0.1% pt/y; p = 0.001) and was higher in patients using standard-dose DOACs (3.1% pt/y) than in those using reduced-dose DOACs (0.4% pt/y). The recurrent VTE rates were similar between the two groups (2.2% pt/y during AC vs. 3% pt/y off AC). CONCLUSION: Physicians' decisions about AC duration were independent of the unprovoked/provoked nature of the index event. The bleeding rate was higher in patients who continued AC using standard-dose DOACs. Surprisingly, the rate of thrombotic recurrence was not different between those who continued or discontinued AC. Randomized studies comparing different procedures to decide on the duration of AC after a first VTE are needed.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Inappropriate Underdosing of Direct Oral Anticoagulants in Atrial Fibrillation Patients: Results from the START2-AF Registry.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients' demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2-2.0), major bleedings (RR 1.8; 95% CI 1.3-1.7), and mortality (RR 2.8; 95% CI 1.9-4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.

MORE EARLY BLEEDS ASSOCIATED WITH HIGH BASELINE DIRECT ORAL ANTICOAGULANT LEVELS IN ATRIAL FIBRILLATION: THE MAS STUDY.

Treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) patients is effective and safe. However, bleeding complications still occur. Whether the measurement of DOAC levels may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" (MAS) Study (#NCT03803579) venous blood was collected 15-30 days after DOAC initiation in AF patients who were then followed for one year to record the occurrence of major and clinically relevant non-major bleeding. DOAC plasma levels were measured in one laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients [957 (57.7%) and 700 treated with standard and low-dose, respectively]. Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (> 0.50); whereas 35 events (2.69% pt/yrs) occurred in those with values in the two lower classes ( 0.50, p= 0.0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first three months of treatment. 19% of patients receiving low doses had standardized activity values in the highest class. More bleeding occurred in patients treated with low (4.3% pt/yrs) than standard (2.2% pt/yrs; p= 0.0160) dose DOAC. Early measurement of DOAC levels in AF patients identified many subjects with high activity levels despite the low doses use and had more bleeding risk during the first 3 months of treatment.