The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism.

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.

Interlaboratory variability in the measurement of direct oral anticoagulants: results from the external quality assessment scheme.

Essentials Tests for direct oral anticoagulants (DOACs) are not widely applied. These tests are perceived to be difficult to run and subjected to large between-lab variation. We carried out proficiency testing surveys for DOAC testing in Italy. Interlab variability was small and similar to that of the international normalised ratio. SUMMARY: Background Tests for direct oral anticoagulants (DOACs) are not widely available. The perception that they are difficult to perform and are subject to large between-laboratory variation makes their implementation difficult. Aims We carried out proficiency-testing surveys for DOACs within the activity of the external quality-assessment scheme of the Italian Federation of Thrombosis Centers. Design Participants were provided with coded freeze-dried plasmas without or with graded concentrations of the three main DOACs, and asked to measure prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time and DOAC concentrations with dedicated tests. The results were centralized for statistical analysis. Results and conclusions All participants (n = 235) reported results for PT and APTT, and approximately one-third reported results for DOAC concentration. PT and APTT showed variable responsiveness to DOACs: PT was more responsive to rivaroxaban than to dabigatran or apixaban. APTT was more responsive to dabigatran than to rivaroxaban or apixaban. The thrombin time ratio (test/normal) was close to unity for plasmas without dabigatran, and was high (i.e. 7.6-fold or 15.4-fold longer than the plasma free from the drug) for plasmas containing dabigatran at low (i.e. 42 ng mL-1 ) or high (i.e. 182 ng mL-1 ) concentration. Dedicated tests were responsive to the respective drugs, and their interlaboratory variability was relatively small (overall coefficients of variation of 8.7%, 8.4% or 10.3% for dabigatran, rivaroxaban and apixaban, respectively) and was comparable to that observed within the same survey for the International Normalized Ratio (i.e. 11.4%). In conclusion, tests for DOAC measurement performed reasonably well in a national quality-control scheme. Regulatory authorities should urgently issue recommendations on their use, and clinical laboratories should make them available.

External validation of the DASH prediction rule: a retrospective cohort study.

Essentials Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE). We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy. A DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model. The DASH score performed better in younger (< 65 years old) subjects. SUMMARY: Background The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort. Aims To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years. Methods Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D-dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D-dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time-dependent analysis. Observed 12-month and 24-month recurrence rates were compared with recurrence rates predicted by the DASH model. Results We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a 'low-risk' (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51-1.45). The c-statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72). Conclusions These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.

European retrospective study of real-life haemophilia treatment.

INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.

Comparison between different D-Dimer cutoff values to assess the individual risk of recurrent venous thromboembolism: analysis of results obtained in the DULCIS study.

INTRODUCTION: D-dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event of venous thromboembolism (VTE). METHODS: Commercial D-dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10. RESULTS: In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age-adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event. CONCLUSION: The results confirm the usefulness of the cutoff levels used in DULCIS.

Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter cohort study.

BACKGROUND: The treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. METHODS: We retrospectively included SVT patients treated with VKAs followed by 37 Italian anticoagulation clinics, until June 2013. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. RESULTS: Three hundred and seventy-five patients were included (median age 53 years; 54.7% males). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% confidence interval [CI], 0.75-2.06) per 100 patient-years. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, the presence of esophageal varices emerged as independent predictor of MB (hazard ratio 5.4; 95% CI, 1.4-21.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years and the mortality rate was 0.83 (95% CI, 0.44-1.54) per 100 patient-years. CONCLUSIONS: Selected SVT patients followed by anticoagulation clinics for the management of VKA treatment show a low rate of major bleeding and vascular events.

Risk of recurrence after a first unprovoked venous thromboembolism: external validation of the Vienna Prediction Model with pooled individual patient data.

BACKGROUND: In order to stratify patients with a first unprovoked venous thromboembolism (VTE) according to their recurrence risk and to identify those who would actually benefit from indefinite anticoagulation, three prediction models have been developed so far; none of them has been yet externally validated. OBJECTIVE: To externally validate the Vienna Prediction Model (VPM), a prediction guide for estimating the recurrence risk after a first unprovoked VTE developed through Cox modeling and including sex, D-dimer and index VTE site as predictors. PATIENTS/METHODS: Nine hundred and four patients pooled from five prospective studies evaluating the prognostic value of D-dimer for VTE recurrence served as the validation cohort. The validity of the VPM in stratifying patients according to their relative recurrence risk (discrimination) and in predicting the absolute recurrence risk (calibration) was tested with survival analysis methods. RESULTS: The ability of the VPM to distinguish patients' risk for recurrent VTE in the validation cohort was at least as good as in the original cohort, with a calibration slope of 1.17 (95% confidence interval 0.71-1.64; P = 0.456 for the hypothesis of a significant difference from 1), and a c-statistic of 0.626 (vs. 0.651 in the original derivation cohort). The VPM absolute predictions in terms of cumulative rates tended to underestimate the observed recurrence rates at 12 months. CONCLUSIONS: By using a pooled individual patient database as a validation cohort, we confirmed the ability of the VPM to stratify patients with a first unprovoked VTE according to their risk of recurrence.

Thrombotic risk in patients with primary immune thrombocytopenia is only mildly increased and explained by personal and treatment-related risk factors.

BACKGROUND: An increased risk of thrombosis has been reported in primary immune thrombocytopenia (ITP) and with the use of thrombopoietin (TPO) receptor agonists, on the basis of population studies using administrative databases. OBJECTIVES: To evaluate if the incidence of venous and arterial thrombosis in patients with primary ITP is higher than a clinically significant cut-off set at of 3% and 6.4%. PATIENTS/METHODS: We undertook a retrospective multicenter investigation in a large cohort of patients requiring at least one treatment for ITP, enrolled from the major tertiary Italian centers treating ITP. A total of 986 patients were analyzed. RESULTS: During a 3888 patient-year follow-up, 43 first thrombotic events occurred: 28 arterial and 15 venous, resulting in a cumulative incidence of 3.2% for arterial (95% CI, 2.0-5.0) and 1.4% (95% CI, 0.8-2.5) for venous thrombosis at 5 years. The annualized rates for 100 patient-years were 1.14 (95% CI, 0.84-1.54), 0.39 (95% CI, 0.23-0.65) and 0.71 (95% CI, 0.49-1.04) for total, venous and arterial thrombosis. Splenectomy, performed in 136 patients (13.7%), increased thrombotic risk (HR = 3.5, 95% CI) compared with non-splenectomized patients. Age > 60 years, more than two risk factors for thrombosis at diagnosis and steroid use were independently associated with an increased risk of thrombosis. CONCLUSIONS: In this study, we demonstrate that the 5-year cumulative incidence of venous and arterial thrombosis in ITP is well below the predefined thresholds. Venous and arterial thromboembolism are not frequent complications in ITP, except in particular settings, such as in splenectomized and elderly patients.

Bleeders, bleeding rates, and bleeding score.

Bleeding symptoms are frequently reported even in otherwise healthy subjects, and differentiating a normal subject from a patient with a mild bleeding disorder (MBD) can be extremely challenging. The concept of bleeding rate, that is, the number of bleeding episodes occurring within a definite time, could be used as the unifying framework reconciling the bleeding risk observed in congenital and acquired coagulopathies into a single picture. For instance, primary prevention trials have shown that the incidence of non-major bleeding symptoms in normal subjects is around five per 100 person-years, and this figure is in accordance with the number of hemorrhagic symptoms reported by normal controls in observational studies on hemorrhagic disorders. The incidence of non-major bleeding in patients with MBDs (e.g. in patients with type 1 VWD carrying the C1130F mutation) is also strikingly similar with that of patients taking antiplatelet drugs, and the incidence in moderately severe bleeding disorders (e.g. type 2 VWD) parallels that of patients taking vitamin K antagonists. The severity of a bleeding disorder may therefore be explained by a bleeding rate model, which also explains several common clinical observations. Appreciation of the bleeding rate of congenital and acquired conditions and of its environmental/genetic modifiers into a single framework will possibly allow the development of better prediction tools in the coming years and represents a major scientific effort to be pursued.

Magnetic resonance imaging and ultrasound evaluation of "healthy" joints in young subjects with severe haemophilia A.

Magnetic resonance imaging (MRI) and ultrasonography (US) are increasingly used in haemophilia A (HA) to detect early joint changes. A total of 40 clinically asymptomatic joints, never involved by bleeding events ["healthy joints" (HJ)], were evaluated by MRI and, in parallel, by US in 20 young subjects with severe HA (22.45 ± 2.72 years old; no history of arthritides, of viral infections or of inhibitors against factor VIII). The same joints were evaluated in 20 matched non-haemophilic (no-HA) subjects (mean age 23.90 ± 2.31 years, P = 0.078 vs. HA subjects). US images were obtained with specific probe positions according to validated procedures. A validated US score and progressive (P-MRI) and additive (A-MRI) MRI scores were employed for data collection and analysis. The US score was higher in HA than in no-HA subjects (3.40 ± 1.72 vs. 0.80 ± 1.10, P < 0.001). Taking into account only moderate/severe alterations, joint effusion was found in 55% of HA and in 5% of no-HA joints (P < 0.001); synovial hypertrophy was found in 20% of HA and in none of the no-HA joints; cartilage erosion was found in 30% of HA and in none of no-HA joints. MRI examinations confirmed these findings and the US score correlated with the A-MRI (r = 0.732, P < 0.001) and with the P-MRI (r = 0.598, P < 0.001) scores. MRI and US data significantly correlated as to effusion (r = 0.819, P = 0.002), synovial hypertrophy (r = 0.633, P = 0.036) and cartilage erosion (r = 0.734, P = 0.010). Despite inherent limitations, joint US examination identified subclinical abnormalities of HJ in young subjects with severe HA.

Phase III studies on novel oral anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results.

In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non-inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low- to moderate-risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1-2.2) whereas rivaroxaban was tested in high-risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs.

Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH).

BACKGROUND: In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence. OBJECTIVES: We aimed to develop a score that could predict the recurrence risk following a first episode of unprovoked VTE, pooling individual patient data from seven prospective studies. METHODS: One thousand eight hundred and eighteen cases with unprovoked VTE treated for at least 3 months with a vitamin K antagonist were available for analysis. Optimism-corrected Cox regression coefficients were used to develop a recurrence score that was subsequently internally validated by bootstrap analysis. RESULTS: Abnormal D-dimer after stopping anticoagulation, age <50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence and were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy) showing a satisfactory predictive capability (ROC area =0.71). The annualized recurrence risk was 3.1% (95% confidence interval [CI], 2.3-3.9) for a score ≤ 1, 6.4% (95% CI, 4.8-7.9) for a score=2 and 12.3% (95% CI, 9.9-14.7) for a score ≥ 3. By considering at low recurrence risk those patients with a score ≤ 1, life-long anticoagulation might be avoided in about half of patients with unprovoked VTE. CONCLUSIONS: The DASH prediction rule appears to predict recurrence risk in patients with a first unprovoked VTE and may be useful to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at least 3 months.

Different bleeding risk in type 2A and 2M von Willebrand disease: a 2-year prospective study in 107 patients.

BACKGROUND: Type 2A and 2M von Willebrand disease (VWD2A and VWD2M) are characterized by the presence of a dysfunctional von Willebrand factor (VWF) and a variable bleeding tendency. So far, a head-to-head comparison of the clinical history and bleeding risk between VWD2A and VWD2M has never been provided in a prospective manner. AIM OF THE STUDY: We assessed the bleeding incidence rate and clinical characteristics in two cohorts of 17 families (46 patients) with VWD2A and 15 families (61 patients) with VWD2M prospectively followed-up for 24 months. VWF gene mutations were characterized in all of them. RESULTS: Mean bleeding score (BS) and VWF antigen at enrollment were significantly higher in VWD2A patients (P = 0.007). No correlation between VWF activity or factor VIII levels and the severity of BS was observed. The incidence rate of spontaneous bleeding requiring treatment was 107/100 patient-years (95% CI, 88.3-131) in VWD2A compared with 40/100 patient-years (95% CI, 30-53) in VWD2M (P < 0.001). The risk of bleeding was significantly higher in patients with BS ≥ 10 at enrollment compared with those with BS 0-2. Furthermore, 54 episodes of gastrointestinal bleeding occurred in 17/46 (36.9%) VWD2A patients and seven in 2/61 (3.3%) VWD2M patients (P < 0.0001). CONCLUSION: Bleeding tendency in VWD2A is greater than that of VWD2M, is not explained by factor VIII or VWF levels and is mainly due to an increased incidence of gastrointestinal bleeding.

Questions and answers on the use of dabigatran and perspectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA).

Dabigatran and other new oral anticoagulants (OAC) represent a step forward in stroke prevention in patients with atrial fibrillation (AF). They indeed have been shown to be an alternative to vitamin K antagonists (VKAs) without the burden of laboratory control. However, these new drugs compete with an effective and well-established therapy, thus bringing about a series of questions and doubts. In this report members of the board of the Italian Federation of Thrombosis Centers (FCSA) answer some questions every clinician might be confronted with.

Prospective evaluation of the clinical utility of quantitative bleeding severity assessment in patients referred for hemostatic evaluation.

BACKGROUND: Quantitative bleeding assessment tools (BATs) have been used to describe the severity of the bleeding phenotype in patients with von Willebrand disease. OBJECTIVES: To evaluate the clinical usefulness of a BAT for the diagnosis of mild bleeding disorders (MBDs) in previously undiagnosed patients. METHODS: We prospectively assessed 215 patients who were consecutively referred for evaluation of bleeding symptoms (n=71), abnormal laboratory clotting test results (n=105) or family investigation (n=39) at two second-level centers. The bleeding history was assessed by a young investigator who administered the BAT instrument, and also by a senior physician who independently evaluated the patient and made the final diagnoses. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were computed for a predefined bleeding score (BS) cut-off (BS of >3). Receiver operating characteristic curves were used to establish a diagnostic prediction rule. RESULTS: Assuming the prevalence of MBD in the general population to be ∼1%, a normal BS (≤3) had a very high NPV (99.2%). The PPVs in patients referred for hemostatic or family evaluation at second-level clinics were estimated to be 71.0% and 77.5% (assuming MDB prevalences of 20% and 50%, respectively, in these settings). Measurement of BS in addition to activated partial thromboplastin time significantly increased the diagnostic efficiency of the BAT instrument (NPV of 99.6%). CONCLUSIONS: BAT use improves the evaluation of patients with suspected MBD, and we propose its use in a clinical prediction guide based on BAT and activated partial thromboplastin time for the exclusion of patients with suspected MBD in a low-prevalence setting.

Carotid plaque morphology improves stroke risk prediction: usefulness of a new ultrasonographic score.

Carotid thickening and plaque detected by B-mode imaging ultrasound are useful to improve the ischemic risk evaluation in asymptomatic subjects over and beyond the traditional cardiovascular risk factors. Some plaque's echographic parameters help describing the vascular risk. We hypothesized that the stenosis degree, plaque surface irregularity, echolucency and texture, compounded in a Total Plaque Risk Score (TPRS), are predictors of the ischemic events in the San Daniele study, a general population-based study of 1,348 subjects followed for 12 years in average. In the 171 subjects with at least one plaque at baseline, high TPRS was the most powerful independent predictor of cerebrovascular events, which occurred in 115 subjects. Addition of plaque characteristics significantly increased the area under the ROC curve (0.90 vs. 0.88, p = 0.04) versus the Framingham risk score alone. The TPRS is a potential new tool to improve the stroke risk prediction.