Patients with antiphospholipid syndrome and a first venous or arterial thrombotic event: clinical characteristics, antibody profiles and estimate of the risk of recurrence.

OBJECTIVES: Thrombosis in antiphospholipid syndrome (APS) involves in most cases the venous circulation. Why in some patients thrombotic APS affects the arterial circulation and in particular cerebral circulation is unknown. In previous studies, both patient characteristics and antiphospholipid antibody types and titers have been associated with arterial thrombosis. Aim of this study was to compare the clinical characteristics and laboratory findings of venous and arterial thrombotic APS from a large series of patients. METHODS: Data were retrieved from the Start 2 antiphospholipid, a multicenter prospective register of long-term collected data from Thrombosis Centers in Italy. RESULTS: Of 167 patients with thrombotic APS, 114 (68 %) had a venous and 53 (32 %) had an arterial event as first clinical manifestation. Several clinical characteristics and risk factors were different among groups in univariate analysis. Using logistic regression analysis, reduced creatinine clearance and hyperlipidemia were independent variable for the occurrence of arterial APS. Notably, no difference in antiphospholipid antibody profiles and aß2-Glycoprotein I levels were found between groups. A higher adjusted global antiphospholipid syndrome score (aGAPSS) was found in arterial group indicating a possible high recurrence rate in arterial APS. CONCLUSIONS: These data have pathophysiological and clinical implication since associated conditions might predispose patients to arterial rather than venous events and call to a close monitoring and treatment of arterial APS due to their increased tendency to recurrence.

Recurrence after stopping anticoagulants in women with combined oral contraceptive-associated venous thromboembolism: A systematic review and meta-analysis.

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.

Bleeding and mortality risk in patients implanted with mechanical prosthetic heart valves with and without thrombocytopenia. Insights from the nationwide PLECTRUM registry.

Previous studies showed that mechanical prosthetic heart valve (MPHV) patients may develop thrombocytopenia, but its association with clinical outcomes has not been investigated. We enrolled 1,663 patients with available platelet count from the multicenter nationwide retrospective PLECTRUM registry to investigate the association of thrombocytopenia with all-cause mortality and major bleeding (MB) in patients implanted with MPHV. Thrombocytopenia was defined by platelet count <150 × 109/L. Overall, 44.9% of patients were women and the mean age was 56.7 years. At baseline, 184 (11.1%) patients had thrombocytopenia. Patients with thrombocytopenia were more frequently men and elderly. Platelet count showed an age-dependent decline in men but not in women. We found an increased risk of death in patients with age ≥ 65 years, with a low anticoagulation quality, concomitant arterial hypertension, heart failure, a higher INR range, or with thrombocytopenia (OR 1.739, 95%CI 1.048-2.886, p = .032). At multivariable logistic regression, patients with age ≥65 years, concomitant AF and thrombocytopenia (OR 1.907, 95%CI 1.219-2.983, p = .005) had an increased risk of MBs. In MPHV patients, thrombocytopenia is associated with an increased risk of death and MB. There is a growing need for a sex- and age-specific threshold to define platelet count in adult patients.

Sex-based difference in anticoagulated patients with mechanical prosthetic heart valves and long-term mortality risk.

BACKGROUND: Vitamin K antagonists (VKAs) reduce thromboembolism in patients with mechanical prosthetic heart valves (MPHV). It is unclear whether a sex-based difference in MPHV patients regarding valve site, anticoagulation quality, and mortality risk does exist. METHODS: We analysed 2111 MPHV patients from the nationwide PLECTRUM study promoted by the Italian Federation of Anticoagulation Clinics (FCSA). We analysed the site of MPHV, anticoagulation quality, as assessed by the time in therapeutic range (TiTR), and mortality risk in women and men. RESULTS: The mean age of the patients was 56.8 ± 12.3 years. Women were older with a lower prevalence of ischemic heart disease and smoking habit and a higher prevalence of atrial fibrillation at baseline. Aortic MPHV was more frequent in men (74.7% vs 43.3%, P < .001), whereas mitral (41.1% vs 17.6%, P < .001) and mitro-aortic (15.6% vs 7.7%, P < .001) MPVH in women. The association between female sex and mitral/mitro-aortic site remained at multivariable logistic regression analysis (Odds Ratio 3.623, 95% Confidence Interval [CI] 2.947-4.455, P < .001). Regarding anticoagulation quality, women showed lower mean TiTR (63.0 ± 19.4 vs 57.5 ± 19.2, P < .001), and a higher proportion of TiTR < 60% (54.9% vs 43.3%, P < .001). During a mean follow-up of 123 months (21 665 pt-years), 152 deaths occurred (0.7%/year); 83 in the aortic (0.63%/year) and 69 in the mitral/mitro-aortic (0.81%/year) group. At multivariable Cox proportional hazard regression analysis, female sex was not associated with mortality (HR 0.953, 95%CI 0.678 1.340, P = .783). CONCLUSIONS: Female sex is independently associated with mitral/mitro-aortic MPHV. Despite a lower TiTR in women, mortality risk did not differ between the two groups.

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.

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study.

Quality of warfarin therapy in patients with a mechanical prosthetic heart valve (MPHV) has been barely investigated. We analysed determinants of low time in the therapeutic range (TiTR <60%) in 2111 patients with MPHVs from the nationwide PLECTRUM study by the Italian Federation of Anticoagulation Clinics. Overall, 48·5% of patients had a TiTR of < 60%. At logistic regression analysis, arterial hypertension (odds ratio [OR] 1·502, P < 0·001), diabetes (OR 1·732, P < 0·001), heart failure (OR 1·484, P = 0·004), mitral site (vs. aortic) (OR 1·399, P = 0·006), international normalised ratio (INR) ranges of 2·5-3·5 (OR 2·575, P < 0·001) and 3·0-4·0 (OR 8·215, P < 0·001) associated with TiTR < 60%. TiTR is substantially suboptimal in MPHV patients, particularly in higher INR ranges.

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.

Unusual hydroxyl effect on fulvene endoperoxide decompositions.

The thermal decomposition of fulvene endoperoxides ordinarily proceeds via an allene oxide intermediate affording oxepin-2(3H)-one derivatives. We have now uncovered new, unusual pathways in these decompositions where the presence of a hydroxyl group on the alkyl or aryl attached to the fulvene exocyclic double bond has a profound effect on the fate of the reactive intermediates derived from the unstable endoperoxides. Computational work supports the proposed mechanistic pathways.

1,2,4-triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies.

The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor.

Erythrocytosis and severe asphyxia: two different causes of neonatal myocardial infarction.

Neonatal acute myocardial infarction is a rare event that carries a high mortality rate. We describe the cases of two newborns who survived acute myocardial infarction and discuss the management. The first neonate was born with severe asphyxia and left ventricular myocardial infarction with ventricular tachycardia. In this patient, systemic flow was maintained by right-to-left shunting through the patent ductus arteriosus. The second neonate presented with a haematocrit of 80% and an inferolateral myocardial infarction. Intensive treatment of low cardiac output syndrome led to survival of both high-risk neonates. In the follow-up, at 48 and 4 months, respectively, ventricular function recovered in both patients.

Renin-angiotensin-aldosterone system inhibitors and mortality risk in elderly patients with atrial fibrillation. Insights from the nationwide START registry.

BACKGROUND: Arterial hypertension is the most common cardiovascular comorbidity in atrial fibrillation (AF). Few studies investigated management strategies of hypertension in AF. MATERIALS AND METHODS: We included 5769 AF patients on oral anticoagulants from the nationwide ongoing Italian START registry. We investigated the prescription of antihypertensive drugs and mortality risk. Subgroup analyses according to sex and major cardiovascular comorbidities were performed. RESULTS: Mean age was 80.8 years, 46.1% were women; 80.3% of patients were hypertensive. Furosemide (30.1%) was the most frequent diuretic followed by hydrochlorothiazide (15.4%) and potassium canrenoate (7.9%). 61.1% received ß-blockers: 34.2% bisoprolol, 6.2% atenolol. Additionally, 36.9% were on angiotensin converting enzyme inhibitors (ACE-I): ramipril (20.9%), enalapril (5.3%) and perindopril (2.8%); 31.7% were on angiotensin receptors blockers (ARBs): valsartan (7.6%) and irbesartan (6.4%). Amlodipine and lercanidipine were prescribed in 14.0% and 2.3%, respectively. ACE-I (p < 0.001), α-blockers (p = 0.020) and Dihydropyridines calcium channel blockers (p = 0.004) were more common in men, while ARBs (p = 0.008), thiazide diuretics (p < 0.001) and ß-blockers (p < 0.001) in women. During 22.61 ± 17.1 months, 512 patients died. Multivariable Cox regression analysis showed that ACE-I (Hazard ratio [HR] 0.758, 95% Confidence Interval [95%CI] 0.612-0.940, p = 0.012) and ARBs (HR 0.623, 95%CI 0.487-0.796, p < 0.001) inversely associated with mortality. ACE-I/ARBs inversely associated with mortality in both sexes and in patients with diabetes. This associastion was evident for ACE-I in patients with previous cardiovascular disease, and for ARBs in HF. CONCLUSION: A lower mortality risk was found in AF patients on ACE-I/ARBs. Different prescription patterns of antihypertensive drugs between men and women do exist.

Anticoagulant Therapy in Pregnant Women with Mechanical Heart Valves: Italian Federation of Centers for Diagnosis and Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

The management of anticoagulant therapy in pregnant women with mechanical heart valves (MHVs) is difficult and often challenging even for clinicians experienced in the field. These pregnancies, indeed, are burdened with higher rates of complications for both the mother and the fetus, compared to those in women without MHVs. The maternal need for an optimal anticoagulation as provided by vitamin K antagonists is counterbalanced by their teratogen effect on the embryo and fetus. On the other hand, several concerns have been raised about the efficacy of heparins in pregnant women with MHVs, considering the high risk of thrombotic complications in these patients. Therefore, numerous clinical issues about the management of pregnant women with MHVs remain unanswered, such as the selection of the best anticoagulant agent, the optimal anticoagulation levels to be achieved and maintained, and the evaluation of long-term effects for both the mother and the fetus. Based on a comprehensive review of the current literature, the Italian Federation of the Centers for the Diagnosis and the Surveillance of the Antithrombotic Therapies (FCSA) proposes experience-based suggestions and expert opinions. Particularly, this consensus document aims at providing practical guidance for clinicians dealing with pregnant women with MHVs, to optimize maternal and fetal outcomes while guaranteeing adequate anticoagulation. Finally, FCSA highlights the need for the creation of multidisciplinary teams experienced in the management of pregnant women with MHVs during pregnancy, delivery, and postpartum, in order to better deal with such complex clinical issues and provide a comprehensive counseling to these patients.

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.

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.

The use of reduced DOAC doses in atrial fibrillation patients does not always lead to good anticoagulation levels and avoid adverse events.

BACKGROUND: The MAS study (Blood Advances 2024) showed that a high proportion of Italian AF patients treated with direct oral anticoagulants (DOACs) receive reduced doses. This sub-analysis of MAS data aimed to analyze the effects of reduced (appropriate or not)- or standard-dose use on DOAC activity assessed at baseline and the occurrence of thrombotic or bleeding complications during follow-up. METHODS: The MAS study design, the methods for DOAC measurement, the results, and the adverse events during follow-up, are described in detail elsewhere. RESULTS: Seven hundred AF patients (42 % of the total 1657) received a reduced dose (considered inappropriate in 140 [20 %]). They were older, more frequently women, with lower body mass index (BMI), hemoglobin levels, and creatinine clearance. They more often had cerebral or cardiovascular diseases, were taking more medications, with higher scores for thrombotic or bleeding risk. Despite the use of low doses, 133 (19.0 %) patients had high standardized C-trough DOAC levels and experienced a high proportion of bleeding events (8.3 % per year). Conversely, some patients (4.7 %) had very low levels, resulting in a high incidence of thrombotic events (6.7 % per year). No difference was detected if the reduced dose was appropriate or not. CONCLUSION: The unpredictable, highly variable inter-individual anticoagulant effect of DOACs may lead to either too low or too high anticoagulant levels, increasing the risk of thrombotic or bleeding events. This is particularly relevant for patients with high-risk conditions, such as those chosen for reduced-dose treatment. Further studies are needed to investigate this important clinical issue.

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.

Anticoagulation in atrial fibrillation. A large real-world update.

INTRODUCTION: In a large nationwide administrative database including ∼35 % of Italian population, we analyzed the impact of oral anticoagulant treatment (OAT) in patients with a hospital diagnosis of non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: Of 170404 OAT-naïve patients (mean age 78.7 years; 49.4 % women), only 61.1 % were prescribed direct oral anticoagulants, DOACs, or vitamin-K antagonists, VKAs; 14.2 % were given aspirin (ASA), and 24.8 % no anti-thrombotic drugs (No Tx). We compared ischemic stroke (IS), IS and systemic embolism (IS/SE), intracranial hemorrhage (ICH), major bleeding (MB), major gastro-intestinal bleeding, all-cause deaths and the composite outcome, across four propensity-score matched treatment cohorts with >15400 patients each. Over 2.9±1.5 years, the incidence of IS and IS/SE was slightly less with VKAs than with DOACs (1.62 and 1.84 vs 1.81 and 1.99 events.100 person-years; HR=0.85, 95%CI=0.76-0.95 and HR=0.87, 95%CI=0.78-0.97). This difference disappeared in a sensitivity analysis which excluded those patients treated with low-dose of apixaban, edoxaban, or rivaroxaban (41.7% of DOACs cohort). Compared with DOACs, VKAs were associated with greater incidence of ICH (1.09 vs 0.81; HR=1.38, 95%CI=1.17-1.62), MB (3.78 vs 3.31; HR=1.14, 95%CI=1.02-1.28), all-cause mortality (9.66 vs 10.10; HR=1.07, 95%CI=1.02-1.11), and composite outcome (13.72 vs 13.32; HR=1.04, 95%CI=1.01-1.08). IS, IS/SE, and mortality were more frequent with ASA or No Tx than with VKAs or DOACs (p<0.001 for all comparisons). CONCLUSIONS: Beyond confirming the association with a better net clinical benefit of DOACs over VKAs, our findings substantiate the large proportion of NVAF patients still inappropriately anticoagulated, thereby reinforcing the need for educational programs.

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.