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Abstract: Treatment with direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is effective and safe. However, bleeding complications still occur. Whether DOAC level measurement may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" study, venous blood was collected 15-30 days after DOAC initiation in patients with AF who were then followed up for 1 year to record the occurrence of major and clinically relevant nonmajor bleeding. DOAC plasma levels were measured in 1 laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients (957 [57.7%] and 700 patients 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 2 lower classes (≤0.50, P = .0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first 3 months of treatment. Overall, 19% of patients receiving low doses had standardized values in the highest class. More bleeding occurred in patients on low (4.3% pt/yrs) vs standard (2.2% pt/yrs; P = .0160) dose DOAC. Early measurement of DOAC levels in patients with AF identified many individuals with high levels despite the low doses use and had more bleeding risk during the first 3 months of treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03803579., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The risk of ischemic events carried by different clusters of type 2 diabetes mellitus (DM) in the setting of secondary prevention is not definite and the association between DM and bleeding complications is controversial. We explored these issues in the START-ANTIPLATELET, a multicenter Italian registry including acute coronary syndrome (ACS) patients. Study outcome was 1-year incidence of the net composite endpoint including major adverse cardiovascular events (MACE) or any bleeding and its individual components across different DM strata (no DM, DM with or without insulin). Out of 951 patients, 20.0% had diabetes not on insulin and 2.5% had diabetes on insulin. The rate of the net composite endpoint was highest in patients receiving insulin (39.4 per 100 person-years vs 11.7 in diabetic patients not on insulin vs 14.0 in those without DM; p = 0.007). In DM, the higher risk of MACE was regardless of insulin use (p = 0.36). Conversely, the increase in bleeding complications was limited to patients on insulin (Hazard Ratio 2.31, 95% CI 0.93-5.71 vs no DM; p = 0.0105 across DM strata). On top of aspirin, the rates of the net composite endpoint were similar with ticagrelor/prasugrel or clopidogrel irrespective of DM status (p for interaction 0.63). In conclusion, in ACS patients, type 2 DM enhances the risk of MACE regardless of the DM cluster, whereas the propensity to bleeding related to DM seems confined to insulin-treated patients., (© 2021. Società Italiana di Medicina Interna (SIMI).)

Optimal dual antiplatelet therapy (DAPT) strategy in high-bleeding risk (HBR) patients presenting with acute coronary syndrome remains debated. We sought to investigate the use of clopidogrel versus ticagrelor in HBR patients with acute coronary syndrome and their impact on ischemic and bleeding events at 1 year. In the START-ANTIPLATELET registry (NCT02219984), consecutive patients with ≥ 1 HBR criteria were stratified by DAPT type in clopidogrel versus ticagrelor groups. The primary endpoint was net adverse clinical endpoints (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. Of 1209 patients with 1-year follow-up, 553 were defined at HBR, of whom 383 were considered eligible for the study as on DAPT with clopidogrel (174 or 45.4%) or ticagrelor (209 or 54.6%). Clopidogrel was more often administered in patients at increased ischemic and bleeding risk, while ticagrelor in those undergoing percutaneous coronary intervention. Mean DAPT duration was longer in the ticagrelor group. At 1 year, after multivariate adjustment, no difference in NACEs was observed between patients on clopidogrel versus ticagrelor (19% vs. 11%, adjusted hazard ratio 1.27 [95% CI 0.71-2.27], p = 0.429). Age, number of HBR criteria, and mean DAPT duration were independent predictors of NACEs. In a real-world registry of patients with acute coronary syndrome, 45% were at HBR and frequently treated with clopidogrel. After adjustment for potential confounders, the duration of DAPT, but not DAPT type (stratified by clopidogrel vs. ticagrelor), was associated with the risk of ischemic and bleeding events at 1 year.

The protective effect of obesity on mortality in acute coronary syndromes (ACS) patients remains debated. We aimed at evaluating the impact of obesity on ischemic and bleeding events as possible explanations to the obesity paradox in ACS patients. For the purpose of this substudy, patients enrolled in the START-ANTIPLATELET registry were stratified according to body mass index (BMI) into 3 groups: normal, BMI <25 kg/m 2 ; overweight, BMI: 25 to 29.9 kg/m 2 ; obese, BMI ≥30 kg/m 2 . The primary end point was net adverse clinical end points (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. In n = 1,209 patients, n = 410 (33.9%) were normal, n = 538 (44.5%) were overweight and n = 261 (21.6%) were obese. Compared to the normal weight group, obese and overweight patients had a higher prevalence of cardiovascular risk factors but were younger, with a better left ventricular ejection fraction and lower PRECISE-DAPT score. At 1-year follow-up net adverse clinical endpoints was more frequently observed in normal than in overweight and obese patients (15.1%, 8.6%, and9.6%, respectively; p = 0.004), driven by a significantly higher rate of all-cause death (6.3%, 2.6%, and 3.8%, respectively; p = 0.008), whereas no significant differences were noted in terms of myocardial infarction, stroke, and major bleeding. When correcting for confounding variables, BMI loses its power in independently predicting outcomes, failing to confirm the obesity paradox in a real-world ACS population. In conclusion, our study conflicts the obesity paradox in real-world ACS population, and suggest that the reduced rate of adverse events and mortality in obese patients may be explained by relevant differences in the clinical risk profile and medications rather than BMI per se., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment., Background: Direct oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF)., Methods: Five hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated., Results: Two hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding., Conclusions: Bleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Direct oral anticoagulants (DOACs) have shown similar efficacy and safety with respect to warfarin in patients with atrial fibrillation (AF). However, the proportion of patients aged ≥85 years enrolled in clinical trials was low and the applicability of their results to very elderly patients is still uncertain. We have carried out a prospective cohort study on AF patients aged ≥85 years enrolled in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) and treated with either VKAs or DOACs, with the aim to evaluate mortality, bleeding and thrombotic rates during a long-term follow-up. We enrolled 1124 patients who started anticoagulation at ≥85 years with VKA (58.7%) or DOACs (41.3%), Clinical characteristics of patients were similar, except for a higher prevalence of coronary artery disease and renal failure in VKAs patients and of a history of previous bleeding and previous stroke/TIA in patients on DOACs. Median CHA2DS2VASc and HAS-BLED scores were similar between the two groups. During follow-up, 47 major bleedings (rate 2.3 x100 pt-yrs) and 19 stroke/TIA (0.9 x100 pt-yrs) were recorded. The incidence of bleeding was similar between patients on VKAs and DOACs. Patients on DOACs showed a higher rate of thrombotic events during treatment (rate 1.84 and 0.50,respectively). Mortality rate was higher in patients on VKAs than in patients on DOACs (HR 0.64 (95% CI 0.46-0.91). In conclusion, we confirm the overall safety and effectiveness of anticoagulant treatment in very elderly AF patients, with lower mortality rates in DOACs patients, similar bleeding risk, and a higher risk for cerebral thrombotic events in DOACs patients., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: D.P. has received honoraria from Boehringer-Ingelheim, BMS-Pfizer, Daiichi-Sankyo; W.A. has received honoraria from Boehringer Ingelheim, Bayer Pharmaceuticals, BMS-Pfizer and Daiichi-Sankyo, Research support from Bayer Pharmaceuticals and Boehringer Ingelheim; Gu.Pa. has sat on advisory boards for Alfasigma, Pfizer, BMS and Roche, and has received speaker’s fees from Werfen, outside the submitted work; S.T. has received honoraria from Bayer Pharmaceuticals, Boehringer Ingelheim, Stago, Daiichi, BMS-Pfizer, Sobi, CSL Behring, Roche; E.A., Lu.Mi., L.M., Gi.Pi. none declared. work. The competing interest declared does not alter our adherence to PLOS ONE policies on sharing data and materials.

The management of major bleeding in patients treated with direct oral anticoagulants (DOACs) is still not well established. START-Events, a branch of the START registry (Survey on anTicoagulated pAtients RegisTer) (NCT02219984), aims to describe the actual management of bleeding or recurrent thrombotic events in routine clinical practice. We here present the results of the management of bleeding patients. The START-Event registry is a prospective, observational, multicenter, international study. Baseline characteristics (demographic, clinical, risk factors) of patients, laboratory data at admission and during follow-up, site of bleeding, therapeutic strategies, and outcomes at the time of hospital discharge and after 6 months were recorded on a web-based case report form. Between January 2015 and December 2016, 117 patients with major bleeding events were enrolled. Non-valvular atrial fibrillation (NVAF) was the indication for treatment in 84% (62% males); 53 patients had intracranial bleeding (13 fatal), 42 had gastrointestinal bleeding (1 fatal), and 22 had bleeding in other sites. Therapeutic interventions for the management of bleeding were performed in 71% of patients. Therapeutic strategies with/without surgery or invasive procedures included: fluid replacement or red blood cells transfusion, prothrombin complex concentrates (3 or 4 factors), antifibrinolytic drugs, and the administration of idarucizumab. Creatinine, blood cell count, and PT/aPTT were the most frequent tests requested, while specific DOAC measurements were performed in 23% of patients. Mortality during hospitalization was 11.9%, at 6-month follow-up 15.5%. Our data confirm a high heterogeneity in the management of bleeding complications in patients treated with DOACs.

Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding., Summary: Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: Patients with a mechanical prosthetic heart valve implantation need to be treated with a vitamin K antagonist (VKA) due to a substantially high risk of thromboembolism. In this study we report data on patients with mechanical heart valves (MV), with the aim of evaluating the thromboembolic risk in relation to the type and site of implantation, quality of anticoagulation and risk factors associated with thromboembolism., Methods: Observational retrospective multicenter study among Centers affiliated to the Italian Federation of Anticoagulation Clinics (FCSA) on patients with MV implanted after 1990 and followed for the management of anticoagulation., Results: We analyzed 2357 patients with mechanical heart valves (55.2% males), followed for 24,081 years. During the follow-up, 164 thromboembolic events (0.67/100 pt-yrs) and 243 major bleedings (1.0/100 pt-yrs) occurred. The median Time in Therapeutic Range (TTR), calculated in all intended INR classes, was 60% (IQR 47-74%). The rates of thrombotic events were significantly higher in patients intended to stay at therapeutic ranges >INR 2.0-3.0. The presence of atrial fibrillation, history of thromboembolism and of mitral prosthesis were independently associated with thromboembolism. However, a bad quality of anticoagulation (TTR <47%, 25°percentile of our population) was not correlated with thromboembolism., Conclusions: A low rate of bleeding and thromboembolic events in patients with mechanical heart valves were found, despite the sub-optimal anticoagulation control. The thromboembolic risk was not associated with the low TTR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chronic renal failure (CRF) impairs prognosis in patients with acute coronary syndromes (ACS); the differential impact of CRF on ischemic and bleeding events in the setting of ACS is unclear. We explored the predictive role of CRF, identified by different equations for the glomerular filtration rate estimation, on the occurrence of the composite end point, including both ischemic cardiovascular and major bleeding (major adverse cardiovascular and bleeding events [MACBE]) at 1 year, and its components. We accessed each patients data from 718 participants in the prospective, multicenter, and START ANTIPLATELET registry, performed on patients with ACS. The ability to predict the risk of MACBE was modest and similar for Cockcroft-Gault, MDRD, and CKD-EPI equations (area under the curves: 0.55, 95% confidence interval [CI] 0.47 to 0.63; 0.53, 95% CI 0.45 to 0.61; 0.54, 95% CI 0.46 to 0.62; respectively, overall p = 0.63). The incidence of MACBE in patients with CRF was 12.6 versus 7.4 per 100 patients/year in those with preserved renal function (adjusted odds ratio [OR] 1.80, 1.02 to 3.20, p = 0.045); the absolute excess in events rate due to CRF was higher for ischemic events (3.5%) than for major bleeding (2.6%). The increased occurrence of MACBE was even greater in patients with CRF and concomitant anemia (OR 2.16) and in patients with severe CRF (OR 2.78). In conclusion, our study indicates that, in patients with ACS, CRF impairs the clinical outcome at 1 year, especially when severe and when is concomitant with anemia. CRF is associated with greater absolute increase of ischemic events than major bleeding., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: The issue of anticoagulation in individuals with nonvalvular atrial fibrillation (NVAF) and 1 non-gender-related (NGR) risk factor is subject to debate. The reported risk of stroke in untreated individuals is not uniform, and the rate of hemorrhage associated with anticoagulation in this group of individuals is not well defined. To this end, we assessed the rate of stroke and major hemorrhage in individuals treated with warfarin., Materials and Methods: individuals were extracted from the START register, an observational, multicenter, dynamic inception cohort study that collects data on NVAF individuals starting anticoagulation therapy. Risk of stroke is stratified using the CHA 2 DS 2 VASc score upon entry into the registry., Results: Overall, 431 individuals with 1 NGR risk factor were followed up for 604 person-years. One nonfatal ischemic stroke was recorded (0.17 per 100 person-years) during follow-up. On the other hand, there were 9 major bleeding events (1.49 per 100 person-years), with 4 being intracranial hemorrhage (0.66 per 100 person-years), 1 of which was fatal. No difference in patient characteristics, bleeding risk factors, and quality of treatment were found between individuals who bled versus those who did not. However, a trend toward more bleeding events was observed in individuals <65 years old., Conclusion: We found an elevated risk of major bleeding and intracranial hemorrhage in NVAF individuals treated with warfarin with 1 NGR risk factor for stroke. These data call for caution when treating with warfarin these individuals., (© 2017 John Wiley & Sons Ltd.)

Anticoagulation is recommended in patients with atrial fibrillation (AF) for stroke prevention, and the bleeding risk associated suggests the need for a bleeding risk stratification. HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio (INR), elderly >65 years, drugs/alcohol concomitantly) score includes "labile INR" referred to quality of anticoagulation. However, in naïve patients, this item is not available. In addition, stroke and bleeding risk prediction scores shared several risk factors. The aims of our study were as follows: (1) to evaluate if the HAS-BLED score in its refined form excluding "labile INR" (HAS-BED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, elderly, drugs/alcohol]) is still associated with bleeding risk and (2) to evaluate the predictive ability for bleeding of both stroke and bleeding prediction models. We followed an inception cohort of 4,579 patients with AF enrolled in the Survey on anticoagulaTed pAtients RegisTer (NCT02219984). Major bleeds were recorded. During follow-up (7,014 patient-years), 115 patients experienced a major bleeding (MB; rate 1.6 × 100 patient-years). Patients at high risk were better identified by HAS-BLED and HAS-BED scores with respect to CHADS 2 (congestive heart failure, hypertension, age >75 years, diabetes, previous stroke or transient ischemic attack) and CHA 2 DS 2 VASc (congestive heart, failure, hypertension, age [>75 years], diabetes, stroke/transient ischemic attack, vascular disease, age [65 to 74 years], female gender). HAS-BLED has a slightly higher c value in comparison to CHADS 2 and CHA 2 DS 2 VASc. However, among naïve patients, the predictive ability for hemorrhage of HAS-BED score is overlapping with CHADS 2 and CHA 2 DS 2 VASc. In low stroke risk patients (CHA 2 DS 2 VASc = 0 to 1), only 6 patients are at high bleeding risk, and none of them experienced MB. In conclusion, in our prospective cohort of patients with AF, we found that HAS-BLED and HAS-BED scores identify patients at high bleeding risk. However, the predictive value for MB of HAS-BED used in naïve patients is similar to CHADS 2 or CHA 2 DS 2 VASc, suggesting that stroke stratification scores could be sufficient for tailoring treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The prevalence of AF is higher in men and increases with age. However, the number of elderly women is higher than that of elderly men, and AF should be considered to affect men and women equally. Little information exists on elderly AF patients, and in particular, whether stroke and bleeding risk differs between elderly women and elderly men remains unknown., Methods: We have performed the EPICA Study, a large, multicentre observational study including 4093 elderly patients who started VKA treatment after the age of 80years. In this study, we will focus our analysis on 3015 AF patients followed for 7620 patient-years (pt-yrs) to evaluate if bleeding and stroke risks were different between genders., Results: During follow-up, we recorded 112 ischemic cerebral events (rate 1.5 ×100pt-years) with no difference between genders. History of previous stroke/TIA, hypertension and artery vascular disease are independently associated with stroke/TIA during treatment. We recorded 132 major bleeds (rate 1.7 ×100pt-years); males showed a higher risk of bleeding (OR 1.5), even if not statistically significant. At multivariate analysis, history of major bleeds, history of falls and active cancer are risk factors independently associated to bleeding., Conclusion: Elderly patients with AF do not show clear gender related differences in the risk of major adverse events. However, elderly males showed a higher rate of bleeding complications, and females showed a slightly higher rate of stroke, thus suggesting the possibility of a higher net clinical benefit of anticoagulant treatment in females., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Vitamin K antagonists (VKA) therapy is increasingly used in elderly for prevention of venous thromboembolism (VTE) and of stroke in atrial fibrillation (AF). Glomerular filtration rate (GFR), usually estimated from different equations, decreases progressively with age and it is a risk factor for bleeding. In the frame of the EPICA study, a multicentre prospective observational study including 4,093 patients ≥80 years naïve to VKA treated for AF or after VTE, we performed this ancillary study to evaluate the prevalence of chronic kidney diseases (CKD) by estimated GFR (eGFR). Incidence of bleedings was recorded and bleeding risk was evaluated in relation to eGFR calculated by Cockroft-Gault (C-G); Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In addition, the agreement among the three eGFR formulas was evaluated. We recorded 179 major bleedings (rate 1.87 x100 patient-years [py]), 26 fatal (rate 0.27 x100 py). Moderate CKD was detected in 69.3%, 59.3% and 47.0% and severe CKD in 5.8%, 7.4% and 10.0% of cases by C-G, MDRD and CKD-EPI, respectively. Bleeding risk was higher in patients with severe CKD irrespective of the applied equation. This study confirms that CKD represents an independent risk factor for bleeding and that a wide proportion of elderly on VKA had severe or moderate CKD, suggesting the need for frequent monitoring. Although the different available equations yield different eGFR, all appear to similarly predict the risk of major bleeding.

Introduction: Systemic embolism is the most serious complication of cardioversion of atrial fibrillation (AF) and the immediate post-cardioversion period is associated with increased risk for thrombus formation. For this reason, treatment with vitamin K antagonist (VKA) is recommended for patients with AF. No information is available about bleeding risk related to this practice., Methods: We performed a prospective multicentre study on 242 low-risk AF patients (CHADS(2) score 0-1) that started on warfarin for elective cardioversion to evaluate their bleeding risk., Results: 178 were males (73.6%), mean age 63.9 ± 9.8 years, 60 patients (25%) were aged ≤ 59 years. Patients with CHADS(2) score = 0 were 73 (30%), those with CHADS(2) score = 1 were 169 (70%). Patients were on VKA treatment, maintained at INR intended therapeutic range 2.0-3.0, for a median time of 159 days (range 30-631)total follow-up period 127 patient-years (pt-yrs). Quality of anticoagulation and occurrence of bleeding events were recorded. Patients spent 23%, 64% and 8% of time below, within and above the intended therapeutic range, respectively. When we observed the INR levels, we found that 62 patients (25.6%) had INR>4.5 at least in one occasion, and 23 (9.5%) in ≥ 2. During follow-up, 2 patients had major bleeds (rate 1.6% pt-yrs), one fatal. No embolic complications were recorded., Conclusion: Our results show that low-risk AF patients, treated with VKA for elective cardioversion, carry a not irrelevant risk of bleeding. Efforts are required to properly select patients who could benefit from this procedure, reducing the time of warfarin exposure., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: All stroke risk stratification schemes categorize a history of stroke as a "truly high" risk factor. Therefore, stratifying stroke risk in atrial fibrillation (AF) should perhaps concentrate on primary prevention. However, the risk factors for stroke also lead to an increase in the risk of bleeding. Our objective was to evaluate the agreement among the currently used stroke risk stratification schemes in "real-world" patients with AF in the primary prevention setting, their correlation with adverse events recorded during warfarin treatment, and the relationship between stroke and bleeding risk., Methods: We prospectively followed up 3,302 patients with AF taking warfarin for primary prevention. Stroke risk was assessed using the CHADS(2) (congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke or transient ischemic attack), Atrial Fibrillation Investigators, American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy, American College of Cardiology/American Heart Association/European Society of Cardiology, and National Institute for Health and Clinical Excellence schemas, and for bleeding risk, the outpatient bleeding risk index was calculated. Bleeding and thrombotic events occurring during follow-up were recorded., Results: Patients classified into various stroke risk categories differed widely for different schemes, especially for the moderate- and high-risk categories. The rates of bleeding and thrombotic events during follow-up were 1.24 and 0.76 per 100 patient-years, respectively. All stroke stratification schemes correlated closely to bleeding risk. Stroke rate increased progressively from low- to moderate- to high-risk patients., Conclusions: Stroke risk stratification models differed widely when categorizing subjects into the moderate- and high-stroke-risk categories. Bleeding and stroke risk were closely correlated and both were low among low-risk patients and were similarly high among moderate/high-risk groups.

Background: Vitamin K antagonist (VKA) therapy is increasingly being used for the prevention of venous thromboembolism and stroke in atrial fibrillation. Bleeds are the major concern for VKA prescription, especially in very old patients who carry many risk factors for bleeding. We performed a large multicenter prospective observational study that enrolled very old patients to evaluate the quality of anticoagulation and the incidence of bleedings., Methods and Results: The study included 4093 patients ≥80 years of age who were naïve to VKA for thromboprophylaxis of atrial fibrillation or after venous thromboembolism. Patients' demographic and clinical data were collected, and the quality of anticoagulation and the incidence of bleeding were recorded. The follow-up was 9603 patient-years; median age at the beginning of follow-up was 84 years (range, 80 to 102 years). We recorded 179 major bleedings (rate, 1.87 per 100 patient-years), 26 fatal (rate, 0.27 per 100 patient-years). The rate of bleeding was higher in men compared with women (relative risk, 1.4; 95% confidence interval, 1.12 to 1.72; P=0.002) and among patients ≥85 years of age compared with younger patients (relative risk, 1.3; 95% confidence interval, 1.0 to 1.65; P=0.048). Time in therapeutic range was 62% (interquartile range, 49% to 75%). History of bleeding, active cancer, and history of falls were independently associated with bleeding risk in Cox regression analysis., Conclusion: In this large study on very old patients on VKA carefully monitored by anticoagulation clinics, the rate of bleedings was low, suggesting that age in itself should not be considered a contraindication to treatment. Adequate management of VKA therapy in specifically trained center allows very old and frail patients to benefit from VKA thromboprophylaxis.

Objectives: We sought to evaluate the rate of bleeding in relation to age (<80 and > or =80 years), the quality of anticoagulation (expressed as time spent in international normalized ratio therapeutic range), and factors associated with bleeding events., Background: Stroke prevention in patients with atrial fibrillation (AF) is an increasingly crucial public health target, particularly in patients ages > or =80 years., Methods: We conducted a prospective observational study on 783 patients with AF on oral anticoagulant treatment (OAT)., Results: Patients spent a median 14%, 71%, and 15% of time below, within, and above the intended therapeutic range, respectively. No difference in OAT quality was found between patients age <80 and > or =80 years. During follow-up, 94 patients experienced bleeding complications (rate 3.7 x 100 patient/years), 37 major (rate 1.4 x 100 patient/years), and 57 minor (rate 2.2 x 100 patient/years). Different rates of major hemorrhage were observed between patients age <80 and > or =80 years (0.9 vs. 1.9 x 100 patient/years; p = 0.004). Bleeding risk also was greater in patients with a history of previous cerebral ischemic event (odds ratio [OR]: 2.5; 95% confidence interval: 1.3 to 4.8; p = 0.007). A Cox regression analysis confirmed age > or =80 years associated with bleeding risk (OR: 2.0)., Conclusions: These results indicate that the rate of major bleeding complications may be kept acceptably low also in very elderly AF patients on OAT, provided a careful management of anticoagulation is obtained.

Aims: In atrial fibrillation (AF) patients, age >or=75 years is one of the major risk factors for stroke. However, it is not clear if an upper limit for the indication to OAT exists., Methods and Results: For this reason, we performed a prospective study on 290 AF patients on OAT aged >or=75 years (median age 82 years, total follow-up period 814 pt/years) followed by our Anticoagulation Clinic. Seventeen major bleeding events were recorded (rate 2.1 x 100 pt/years), 11 of which cerebral (1.35 x 100 pt/years). The occurrence of major bleedings was associated with history of previous TIA or stroke [OR 3.4 (1.1-12.5), p=0.01] and with diabetes [OR 4.4 (1.3-14.7) p=0.01]. We found a trend to a progressive increase in the rate of bleeding risk with the increase of the CHADS2 score: patients with score 4-6 showed a rate of 3.4 x 100 pt/years with respect to 1.5 x 100 pt/years of patients with lower score. Number Needed to Harm (NNH) was calculated in relation to different classes of age (75-89, 80-84, >or=85 years) and to CHADS2 score. For patients in CHADS2 score 1-3 NNH remained stable across the different age classes. Instead for patients in CHADS2 score 4-6, NNH varied among the 3 groups of ages, reaching a value of 10 in patients >or=85 years., Conclusion: Our data suggest that: 1) in AF patients older than 75 years with CHADS2 score 1-3 the risk of bleeding is low, 2) in AF patients >85 years with CHADS2 4-6 the risk of bleeding is high so that the use of OAT should be highly individualised.

Over past years, there has been a world-wide increase in oral anticoagulant treatment (OAT). This study was aimed at evaluating the efficacy and safety of OAT managing in a real-practice situation. Nine hundred and three consecutive unselected patients referred for the control of OAT to the Anticoagulation Clinic of the University of Florence were studied. The total follow-up period was 1679 patient-years. The rate of total, major and fatal bleeding events was 5.0, 1.1 and 0.06 per 100 patient-years, respectively. In patients with a target International Normalized Ratio (INR) > or = 3, a significantly higher rate of bleeding (P = 0.02) with respect to patients with a target INR < 3 was observed. The rate of all thrombotic events was 3.8 per 100 patient-years. The rate of major and fatal thrombotic events were 2.4 and 0.4 per 100 patient-years, respectively. At INR >/= 4.5 the rate of bleeding was significantly higher (P = 0.005) than at lower INR. At INR < 2 the rate of all thrombotic events was significantly higher (P = 0.00001) with respect to more elevated intensities of anticoagulation. A low incidence of complications may be obtained even in elderly outpatients on OAT followed at an anticoagulation clinic.

Background: Over the last years, the use of oral anticoagulant treatment (OAT) has increased dramatically, principally for the prevention of embolic stroke in patients with atrial fibrillation. This study was aimed at evaluating the efficacy and safety of the management of OAT in a real-practice situation., Methods: Nine hundred and three consecutive unselected patients, 250 of whom with atrial fibrillation, referred for the control of OAT to the Anticoagulation Clinic of the University of Florence were studied. The total follow-up period was 1679 patient-years., Results: The rate of major bleeding events was 0.8 per 100 patient-years in atrial fibrillation patients. In patients with a target INR > or = 3 a significantly higher rate of bleeding (p = 0.02) with respect to patients with a target INR < 3 was observed., Conclusions: A low incidence of complications may be obtained even in elderly atrial fibrillation patients on OAT followed in an Anticoagulation Clinic specifically devoted to this management.