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Validation of a score for predicting fatal bleeding in patients receiving anticoagulation for venous thromboembolism

Open AccessPublished:July 11, 2013DOI:https://doi.org/10.1016/j.thromres.2013.06.019

      Summary

      Background

      The only available score to assess the risk for fatal bleeding in patients with venous thromboembolism (VTE) has not been validated yet.

      Methods

      We used the RIETE database to validate the risk-score for fatal bleeding within the first 3 months of anticoagulation in a new cohort of patients recruited after the end of the former study. Accuracy was measured using the ROC curve analysis.

      Results

      As of December 2011, 39,284 patients were recruited in RIETE. Of these, 15,206 had not been included in the former study, and were considered to validate the score. Within the first 3 months of anticoagulation, 52 patients (0.34%; 95% CI: 0.27-0.45) died of bleeding. Patients with a risk score of <1.5 points (64.1% of the cohort) had a 0.10% rate of fatal bleeding, those with a score of 1.5-4.0 (33.6%) a rate of 0.72%, and those with a score of >4 points had a rate of 1.44%. The c-statistic for fatal bleeding was 0.775 (95% CI 0.720-0.830). The score performed better for predicting gastrointestinal (c-statistic, 0.869; 95% CI: 0.810-0.928) than intracranial (c-statistic, 0.687; 95% CI: 0.568-0.806) fatal bleeding. The score value with highest combined sensitivity and specificity was 1.75. The risk for fatal bleeding was significantly increased (odds ratio: 7.6; 95% CI 3.7-16.2) above this cut-off value.

      Conclusions

      The accuracy of the score in this validation cohort was similar to the accuracy found in the index study. Interestingly, it performed better for predicting gastrointestinal than intracranial fatal bleeding.

      Abbreviations:

      VTE (VenousTthromboembolism), RIETE (Registro Informatizado de Enfermedad tromboEmbolica), LMWH (Low Molecular Weight Heparin), DVT (Deep Vein Thrombosis), PE (Pulmonary Embolism), VKA (Vitamin K Antagonists), ROC (Receiver Operating Characteristics)

      Keywords

      Introduction

      Venous thromboembolism (VTE) is a commonly diagnosed condition with significant morbidity and mortality [
      • Kearon C.
      • Akl E.A.
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      Antithrombotic therapy for VTE disease. Antithrombotic therapy and prevention of thrombosis (9th Edition): American College of Chest Physicians evidence-based clinical practice guidelines.
      ]. Current guidelines recommend patients with VTE to be initially treated with low-molecular-weight heparin (LMWH), unfractionated heparin or fondaparinux, followed by long-term anticoagulation, which is usually accomplished with vitamin K antagonists (VKA) [
      • Lagerstedt C.I.
      • Olsson C.G.
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      Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis.
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      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      ]. Recommendations for long-term therapy are based on randomized clinical trials [
      • Lagerstedt C.I.
      • Olsson C.G.
      • Fagher B.O.
      • Oqvist B.W.
      • Albrechtsson U.
      Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis.
      ,
      • Hull R.
      • Delmore T.
      • Genton E.
      • Hirsh J.
      • Gent M.
      • Sackett D.
      • et al.
      Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis.
      ,
      • Levine M.N.
      • Hirsh J.
      • Gent M.
      • Turpie A.G.
      • Weitz J.
      • Ginsberg J.
      • et al.
      Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.
      ,
      • Kearon C.
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      • Anderson D.R.
      • Wells P.
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      • et al.
      Extended Low-Intensity Anticoagulation for Thromboembolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thrombo-embolism.
      ,
      • Ridker P.M.
      • Goldhaber S.Z.
      • Danielson E.
      • Rosenberg Y.
      • Eby C.S.
      • Deitcher S.R.
      • et al.
      Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism.
      ,
      • Schulman S.
      • Rhedin A.S.
      • Lindmarker P.
      • Carlsson A.
      • Lärfars G.
      • Nicol P.
      • et al.
      A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.
      ,
      • Agnelli G.
      • Prandoni P.
      • Santamaria M.G.
      • Bagatella P.
      • Iorio A.
      • Bazzan M.
      • et al.
      Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin optimal Duration Italian Trial Investigators.
      ,
      • Pinede L.
      • Ninet J.
      • Duhaut P.
      • Chabaud S.
      • Demolombe-Rague S.
      • Durieu I.
      • et al.
      Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf vein thrombosis.
      ,
      • Agnelli G.
      • Prandoni P.
      • Becattini C.
      • Silingardi M.
      • Taliani M.R.
      • Miccio M.
      • et al.
      Extended oral anticoagulant therapy after a first episode of pulmonary embolism.
      ] that assessed relevant outcomes like VTE recurrences and major bleeding rates, because most trials were underpowered to assess fatal VTE or fatal bleeding events. Furthermore, a number of patients are often excluded from randomized trials of anticoagulation because of co-morbid conditions, short life expectancy, pregnancy or contraindications to therapy, which means that treatment regimens based on the results from randomized clinical trials might not be generalisable to all patients with VTE.
      When weighing the risks and benefits of anticoagulation in an individual patient, in addition to considering the absolute risk of VTE recurrences and major bleeding, the mortality associated with each of these outcomes should be considered. While a number of prognostic models have the potential to predict the risk for major bleeding [
      • Landefeld C.S.
      • Goldman L.
      Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy.
      ,
      • Kuijer P.M.
      • Hutten B.A.
      • Prins M.H.
      • Büller H.R.
      Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism.
      ,
      • Ruiz-Giménez N.
      • Suárez C.
      • Gonzalez R.
      • Nieto J.A.
      • Todolí J.A.
      • Sampériz A.L.
      • et al.
      Predictive variables for major bleeding events in patients presenting with documented venous thromboembolism. Findings from the RIETE Registry.
      ], little has been done to identify patients at increased risk to die of bleeding during the course of anticoagulation. In a previous study using data from the RIETE registry [
      • Nieto J.
      • Solano R.
      • Ruiz-Ribó M.D.
      • Ruiz-Gimémez N.
      • Prandoni P.
      • Kearon C.
      • et al.
      Fatal Bleeding in patients receiving anticoagulant therapy for venous thromboembolism: Findings from the RIETE registry.
      ], we identified 9 clinical and laboratory variables at baseline that were independently associated with an increased risk for fatal bleeding within the first 3 months of anticoagulation, and built a prognostic score to identify patients at low-, moderate- or high risk. In the current study, we tried to validate this score using a new sample of patients recruited in RIETE after the end of the former study.

      Patients and Methods

      The RIETE (Registro Informatizado de Enfermedad TromboEmbólica) Registry is an ongoing, multicenter, international (Spain, Italy, France, Israel, Portugal, Germany, Switzerland, Czech Republic, Macedonia, United States, Brazil and Ecuador), observational registry of consecutive patients with symptomatic, objectively confirmed, acute VTE [
      • Laporte S.
      • Mismetti P.
      • Décousus H.
      • Uresandi F.
      • Otero R.
      • Lobo J.L.
      • et al.
      Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry.
      ,
      • Monreal M.
      • Falgá C.
      • Valdés M.
      • Suárez C.
      • Gabriel F.
      • Tolosa C.
      • et al.
      Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: Findings from the RIETE Registry.
      ,
      • Sánchez Muñoz-Torrero J.F.
      • Bounameaux H.
      • Pedrajas J.M.
      • Lorenzo A.
      • Rubio S.
      • Kearon C.
      • et al.
      Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis.
      ].
      Consecutive patients with symptomatic, acute deep vein thrombosis (DVT) or pulmonary embolism (PE), confirmed by objective tests (contrast venography or ultrasonography for suspected DVT; pulmonary angiography, lung scintigraphy, or helical computed tomography scan for suspected PE), were enrolled in RIETE. Patients were excluded if they did not receive any anticoagulant therapy or were currently participating in a therapeutic clinical trial with a blinded therapy. All patients provided consent to their participation in the registry, in accordance with local Ethics Committee requirements.
      In the RIETE registry, participating physicians ensured that eligible patients were consecutively enrolled. Data were recorded on to a computer-based case report form at each participating hospital and submitted to a centralized coordinating center through a secure website. The study coordinating center assigned patients with a unique identification number to maintain patient confidentiality and was responsible for all data management. Data quality was regularly monitored electronically, including checks to detect inconsistencies or errors, which were resolved by the local coordinators. Data quality was also monitored by periodic visits to participating hospitals by contract research organizations that compared medical records with the submitted data, and made sure that consecutive patients had been recruited into RIETE.

      Study Outcomes

      Fatal bleeding was defined as any death occurring within 7 days of a major bleeding episode, in the absence of an alternative cause of death. Major bleeding was defined as an overt bleed that required a transfusion of 2 or more units of blood, was retroperitoneal, spinal or intracranial, or was fatal. The causes of death were assigned by their attending physicians.

      Baseline Variables and Score

      The baseline variables registered in RIETE have been described elsewhere [
      • Laporte S.
      • Mismetti P.
      • Décousus H.
      • Uresandi F.
      • Otero R.
      • Lobo J.L.
      • et al.
      Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry.
      ,
      • Monreal M.
      • Falgá C.
      • Valdés M.
      • Suárez C.
      • Gabriel F.
      • Tolosa C.
      • et al.
      Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: Findings from the RIETE Registry.
      ,
      • Sánchez Muñoz-Torrero J.F.
      • Bounameaux H.
      • Pedrajas J.M.
      • Lorenzo A.
      • Rubio S.
      • Kearon C.
      • et al.
      Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis.
      ]. Data were recorded when the qualifying episode of VTE was diagnosed. The 9 independent variables associated with an increased risk for fatal bleeding and the points assigned to each variable are presented in Table 1. The patient’s score is the sum of the points assigned to each variable.
      Table 1RIETE score for fatal bleeding in patients receiving anticoagulation for acute venous thromboembolism
      • Nieto J.
      • Solano R.
      • Ruiz-Ribó M.D.
      • Ruiz-Gimémez N.
      • Prandoni P.
      • Kearon C.
      • et al.
      Fatal Bleeding in patients receiving anticoagulant therapy for venous thromboembolism: Findings from the RIETE registry.
      .
      Points
      Age >75 years1
      Metastatic cancer2
      Immobility ≥4 days
      defined as non-surgical patients who were confined to bed with bathroom privileges for ≥4days in the 2-months prior to VTE diagnosis.
      1
      Recent major bleeding
      major bleeding less than 30days before VTE diagnosis.
      1.5
      Abnormal prothrombin time1
      CrCl < 30 ml/min1
      Platelet Count <100 × 109/L1
      Anemia
      defined as hemoglobin <13g/dL in men or <12g/dL in women.
      1
      Distal DVT-1
      low asterisk defined as non-surgical patients who were confined to bed with bathroom privileges for ≥4 days in the 2-months prior to VTE diagnosis.
      # major bleeding less than 30 days before VTE diagnosis.
      defined as hemoglobin <13 g/dL in men or <12 g/dL in women.

      Treatment and Follow-up

      Patients were managed according to the clinical practice of each participating hospital (i.e., there was no standardization of treatment). The type and dose of anticoagulant therapy, as was the insertion of an inferior vena cava filter, were recorded. After discharge, all patients were followed-up for up to 3 months in the outpatient clinic. During each visit, any signs or symptoms suggesting either DVT or PE recurrences or bleeding complications were noted. Most outcomes were classified as reported by the clinical centers. However, if the staff at the coordinating center was in disagreement on how to classify a reported outcome, that event was reviewed by a central adjudicating committee (less than 10% of events). Patients who had major bleeding or recurrent VTE within 3 months of enrollment remained under surveillance until 3 months of follow-up was completed.

      Statistical Analysis

      Student’s t test and the Mann-Whitney test were used to compare continuous variables. Qualitative variables were compared by the Fisher exact test, and the odds ratio and 95% confidence intervals were calculated. Survival curves were constructed according to the Kaplan-Meyer method. The cut-off points for risk categories of fatal bleeding have been previously reported [
      • Nieto J.
      • Solano R.
      • Ruiz-Ribó M.D.
      • Ruiz-Gimémez N.
      • Prandoni P.
      • Kearon C.
      • et al.
      Fatal Bleeding in patients receiving anticoagulant therapy for venous thromboembolism: Findings from the RIETE registry.
      ]. Receiver Operating Characteristics (ROC) curve analysis and the c-statistic was used to assess the accuracy of the score and to identify the score values with highest combined sensitivity and specificity. SPSS software (version 15, SPSS Inc., Chicago, Illinois) was used for the statistical management of the data, and a two-sided p <0.05 was considered to be statistically significant.

      Results

      As of December 2011, 39,284 patients were recruited into the RIETE registry. Of these, 15,206 had not been included in the former study, and were considered for validating the score. In all, 7,814 patients (51%) initially presented with PE (with or without concomitant DVT) and 7,392 with DVT alone. Their clinical characteristics are shown in Table 2. Most patients (89%) received initial therapy with LMWH, 5.9% received unfractionated heparin, 1.1% thrombolytic therapy, and 2.5% an inferior vena cava filter. For long-term therapy, 10,371 patients (68%) received VKA and 4,011 (26%) had LMWH.
      Table 2Clinical characteristics of patients with and without subsequent fatal bleeding.
      Fatal bleedingNo fatal bleedingp value
      Patients, N5215,154
      Clinical characteristics,
       Gender (males)26 (50%)7,367 (49%)0.89
       Age >75 years24 (46%)5,260 (35%)0.11
       Body weight <70 kg30 (58%)5,544 (37%)0.002
      Underlying diseases,
       Chronic lung disease7 (14%)1,759 (12%)0.66
       Chronic heart disease5 (9.6%)1,079 (7.1%)0.42
       Recent major bleeding2 (3.8%)316 (2.1%)0.30
      Risk factors for VTE,
       Recent immobility ≥ 4 days15 (29%)3,470 (23%)0.32
       Recent surgery5 (9.6%)1,680 (11%)1.00
       Cancer29 (56%)3,439 (23%)<0.001
       Metastatic cancer20 (39%)1,405 (9.3%)<0.001
       Prior VTE3 (5.8%)2,341 (15%)0.054
      Baseline blood tests,
       Anemia32 (62%)5,232 (55%)<0.001
       Platelet count <100 × 109/L6 (12%)374 (2.5%)0.002
       Abnormal prothrombin time9 (17%)1,114 (7.4%)0.013
       CrCl levels <30 ml/min10 (19%)1,119 (7.4%)0.004
      VTE characteristics,
       Symptomatic PE32 (62%)7,782 (51%)0.17
       Bilateral DVT6 (12%)578 (3.8%)0.01
       Distal DVT3 (5.8%)1,728 (11%)0.27
      Initial therapy
       LMWH45 (88%)13,550 (89%)0.50
       Unfractionated heparin3 (5.9%)887 (5.9%)1.00
       Thrombolytics3 (5.9%)158 (1.0%)0.02
       Vena cava filter1 (1.9%)372 (2.5%)1.00
      Long-term therapy
       LMWH17 (33%)3,994 (26%)0.34
       Vitamin K antagonists13 (25%)10,358 (68%)<0.001
      Abbreviations: VTE, venous thromboembolism; CrCl, creatinine clearance; PE, pulmonary embolism; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin.
      Within the first 3 months of anticoagulation, 250 patients (1.64%; 95% CI: 1.45-1.86) had major bleeding complications and 52 (0.34%; 95% CI: 0.27-0.45) died of bleeding. Patients subsequently dying of bleeding more likely had cancer, and more likely presented with anemia, platelet count <100 × 109/L, abnormal prothrombin time or renal insufficiency compared with those with no fatal bleeding (Table 2). The most frequent site of fatal bleeding (19 of 52 fatal bleeds, 36.5%) was gastrointestinal (GI), and the highest mortality occurred after intracranial bleeding (14 of 32 major bleeds, 43.7%), as shown in Table 3. One in every 5 fatal bleeding events occurred after a second episode of major bleeding in the same location.
      Table 3Sites of major and fatal bleeding.
      Fatal bleeding (n = 52)Non-fatal major bleeding (n = 198)Major bleeding (n = 250)
      Gastrointestinal19 (36.5%)62 (31.1%)81 (32.4%)
      Intracranial14 (26.9%)18 (9.1%)32 (12.8%)
      Genitourinary2 (3.8%)26 (13.1%)28 (11.2%)
      Hematoma11 (21.2%)65 (32.8%)76 (30.4%)
      Other6 (11.5%)27 (13.6%)33 (13.2%)
      The rate of fatal bleeding increased in parallel to the patient’s risk score (Table 4). Patients with a risk score of <1.5 points (64.1% of the whole series) had a 0.10% rate of fatal bleeding (10 in 9,748 patients), those with a risk score of 1.5-4.0 (33.6% of patients) a rate of 0.72% (37 in 5,111 patients), and those with a score of >4 had a rate of 1.44% (5 in 347 patients). The c-statistic for fatal bleeding with the continuous score was 0.775 (95% CI: 0.720-0.830). Performance was highest for GI bleeding (0.869; 95% CI: 0.810-0.928) and lowest for intracranial bleeding (0.687; 95% CI: 0.568-0.806), as shown in Table 5. Accuracy of the high risk (>4 points) score for GI, extracranial or intracranial fatal bleeding appears in Table 6.
      Table 4Risk categories (low-, intermediate-, high-) of the patients according to score, and corresponding rates of fatal bleeding.
      PointsAll patients (N = 15,206)Fatal bleeding (N = 52)Fatal bleeding rate per risk category
      -1667 (4.4%)00
      0-0.994,646 (30.6%)2 (3.8%)0.04%
      1-1.994,465 (29.4%)8 (15.4%)0.18%
      2-2.992,774 (18.2%)15 (28.9%)0.54%
      3-3.991,664 (10.9%)13 (25%)0.78%
      4-4.99704 (4.6%)11 (21.2%)1.56%
      5-5.99229 (1.5%)3 (5.8%)1.31%
      6-6.9949 (0.3%)00
      7-7.997 (0.05%)00
      8-8.51 (0.007%)00
      Risk category,
      Low (<1.5)9,748 (64.1%)10 (19.2%)0.10%
      Moderate (1.5-4)5,111 (33.6%)37 (71.2%)0.72%
      High risk (>4)347 (2.28%)5 (9.6%)1.44%
      Table 5C-statistic according to site of bleeding.
      c-statisic95% CIStandard errorn
      Fatal bleeding,
       All sites0.7750.720–0.8300.02852
       Extracranial0.8070.750–0.8640.02938
       Intracranial0.6870.568–0.8060.06114
       Gastrointestinal0.8690.810–0.9280.03019
       Muscular/Hematoma0.7370.630–0.8430.05411
      All-cause death0.8390.828–0.8500.061181
      Major bleeding0.7190.689–0.7490.015250
      Abbreviations: CI, confidence intervals.
      Table 6Accuracy of the high-risk (>4 points) and the cut-off (1.75 points) scores for predicting fatal bleeding.
      AnyGastrointestinalExtracranialIntracranial
      High-risk score (>4 points),
       Sensitivity9.6%15.8%10.5%7.1%
       Specificity97.8%97.7%97.7%97.7%
       Positive predictive value1.4%0.9%1.2%0.35%
       Negative predictive value99.7%99.9%99.8%99.9%
       Positive likelihood ratio4.276.974.653.14
       Negative likelihood ratio0.920.860.920.95
      Cut-off score (1.75 points),
       Sensitivity80.8%94.7%86.8%64.3%
       Specificity64.5%64.4%64.4%64.3%
       Positive predictive value0.8%0.3%0.6%0.2%
       Negative predictive value99.9%100%99.9%99.9%
       Positive likelihood ratio2.272.662.441.80
       Negative likelihood ratio0.300.080.200.56
      The score value with highest combined sensitivity and specificity was 1.75 (Fig. 1). Risk for fatal bleeding was significantly increased above this cut-off point (odds ratio [OR]: 7.6; 95% CI: 3.7-16.2), and most fatal bleeding events (42 of 52, 80.1%) occurred in patients exceeding it. The accuracy of the cut-off score (1.75 points) for GI, extracranial or intracranial fatal bleeding appears in Table 6. The negative predictive value for any fatal bleeding is 99.9% and the negative likelihood ratios for GI and extracranial fatal bleeds is 0.08 and 0.20, respectively (Table 6). The cumulative rate of fatal bleeding using the cut-off point appears in Fig. 2. The majority of patients (18 of 19, 94.7%) dying after GI bleeding (OR: 32.5; 95% CI: 4.6-115.8) and most patients (33 of 38, 86.8%) dying after extracranial bleeding (OR: 12.0; 95% CI 4.5-34.8) had score values above the cut-off point.
      Figure thumbnail gr1
      Fig. 1Receiver operating characteristics curve for any fatal bleeding according to the continuous score (c-statistic 0.775). The black circle represents the position of the cut-off point (score, 1.75) with the highest combined sensitivity (81%) and specificity (64.5%).
      Figure thumbnail gr2
      Fig. 2Cumulative incidence of fatal bleeding according to a cut-off score of 1.75.

      Discussion

      Our findings, obtained from a large series of consecutive patients receiving anticoagulation for acute VTE, confirm the validity of the score. About two-thirds of patients were considered to be at low-risk according to the risk score with a 3-month rate of fatal bleeding of 0.10%, about one-third were considered to be at moderate-risk and had a rate of 0.72%, and about 2% were considered to be at high-risk with a rate of 1.44%. Interestingly, the best cut-off point (score, 1.75, only slightly over the upper limit of the low risk category) correctly identified the subgroup of patients with 7 to 30-fold higher risk for fatal bleeding (depending on sites of bleeding). In patients at high risk for fatal bleeding it may be wise to administer anticoagulants at a lower intensity (or even to withhold anticoagulation and insert a vena cava filter), alter other medications, or monitor therapy and signs of bleeding more closely, as early detection of major bleeding might reduce mortality. On the other hand, our score also identified two in every 3 patients (64.1%) with a very low (0.10%) rate of fatal bleeding, which is also reassuring. Only 10 of 52 patients with fatal bleeds scored less than 1.75 (false negative), what explains the roughly 100% negative predictive value. According to the c-statistic, our score performance was comparable to (or even better than) other well known scores used in clinical practice [
      • Donze J.
      • Rodondi N.
      • Waeber G.
      • Monney P.
      • Cornuz J.
      • Aujesky D.
      Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study.
      ,
      • Apostolakis S.
      • Lane D.A.
      • Guo Y.
      • Buller H.
      • Lip G.Y.H.
      Performance of the HEMORR2HAGES, ATRIA and HAS-BLED Bleeding Risk-Prediction Scores in patients with atrial fibrillation undergoing anticoagulation.
      ] to predict major bleeding in different patient populations.
      Our score had statistically significant value, but should be considered only a first step for better understanding the effect of combined risk factors. Its positive predictive value in patients at high-risk is low (1.4%), and its positive likelihood ratio (4.27) is close to the level for moderate performance [
      • Dahri K.
      • Loewen P.
      The risk of bleeding with warfarin: A systematic review and performance analysis of clinical prediction rules.
      ]. The c-statistic reflects the ability of the prediction model to discriminate the outcome (a value of 1.0 reflects perfect discrimination; 0.5 is no better than chance alone). Thus, it seems to be of value for decision making in clinical practice. Moreover, our score performed better in predicting fatal GI bleeding according to the c-statistic (0.869) and the positive likelihood ratio (6.97), and worse in predicting fatal intracranial bleeding. Thus, our findings suggest that GI and intracranial bleeding may have different risk factors, and may deserve a different approach. Specific risk-factors for intracranial bleeding (i.e., arterial hypertension or previous intracranial bleeding) are not adequately weighed in our score to predict this outcome. Therefore, in order to more precisely assess the risk for fatal bleeding, it would be wise to use specific scores for different sites of bleeding.
      The present study has some potential limitations that should be addressed. First, RIETE does not have a standardized protocol to treat their patients. Thus, physicians treat VTE and bleeding episodes according to local clinical practice. Second, we do not have enough data to assess the influence of elements that may change during the course of the disease, like the INR control, the use of concomitant medications or the presence of intercurrent diseases. Third, the score was validated in a further RIETE cohort, which is not a completely independent patient sample, and therefore, unrecognized flaws that could be present in the previous study may be reproduced in this. However, while only Spanish patients were included in the index study, in the current cohort sample one in every 3 patients was coming from other countries. Finally, the rate of fatal bleeding in the former study was 0.55% (95% CI: 0.47-0.65)14 and in the current study 0.34% (95% CI: 0.27-0.45). A plausible explanation for the lower rate of fatal bleeding in the current study may be the lower proportion of patients with independent predictors for fatal bleeding, such as age over 75 years (46% vs. 63%), recent immobility (29% vs. 47%) or severe renal insufficiency (19% vs. 27%) compared to the former series [
      • Nieto J.
      • Solano R.
      • Ruiz-Ribó M.D.
      • Ruiz-Gimémez N.
      • Prandoni P.
      • Kearon C.
      • et al.
      Fatal Bleeding in patients receiving anticoagulant therapy for venous thromboembolism: Findings from the RIETE registry.
      ]. In contrast, the use of thrombolytics was more frequent in patients with fatal bleeding in this study (3 cases, 5.9%) compared to the original (2 cases, 1.5%). This is a relevant difference between the derivation and the validation cohorts that may explain part of the variation in the score accuracy.
      In summary, the current study validated the accuracy of the fatal bleeding score, and reveals the greatest performance for extracranial bleeds. This score still needs to be validated in an independent patient sample, but it might represent a valid tool for tailoring anticoagulation of VTE patients at high-risk for fatal bleeding.

      Conflict of Interest Statement

      No conflicts of interest that could influence this work were declared.

      Acknowledgements

      We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG’s support was limited to the part of RIETE outside Spain, which accounts for a 18.2% of the total patients included in the RIETE Registry. We also thank the Registry Coordinating Center, S & H Medical Science Service, for their quality control, logistic and administrative support.

      Appendix A.

      Coordinator of the RIETE Registry: Dr. Manuel Monreal (Spain)
      RIETE Steering Committee Members: Dr. Hervè Decousus (France)
      Dr. Paolo Prandoni (Italy)
      Dr. Benjamin Brenner (Israel)
      RIETE National Coordinators: Dr. Raquel Barba (Spain)
      Dr. Pierpaolo Di Micco (Italy)
      Dr. Laurent Bertoletti (France)
      Dr. Sebastian Schellong (Germany)
      Dr. Manolis Papadakis (Greece)
      Dr. Inna Tzoran (Israel)
      Dr. Abilio Reis (Portugal)
      Dr. Marijan Bosevski (R.Macedonia)
      Dr. Henri Bounameaux (Switzerland)
      Dr. Radovan Malý (Czech Republic)
      RIETE Registry Coordinating Center: S & H Medical Science Service
      Members of the RIETE Group: SPAIN: Arcelus JI, Arroyo M, Ballaz A, Barba R, Barrón M, Barrón-Andrés B, Bascuñana J, Bedate P, Blanco-Molina A, Bueso T, Casado I, del Molino F, del Toro J, Falgá C, Fernández-Capitán C, Fole D, Gallego P, García-Bragado F, Gavín O, Gómez V, González J, González-Bachs E, Grau E, Guil M, Guijarro R, Gutiérrez J, Hernández L, Hernández-Huerta S, Jara-Palomares L, Jaras MJ, Jiménez D, Lecumberri R, Lobo JL, López-Jiménez L, López-Sáez JB, Lorente MA, Lorenzo A, Luque JM, Madridano O, Maestre A, Marchena PJ, Martín-Villasclaras JJ, Monreal M, Muñoz FJ, Nauffal MD, Nieto JA, Núñez MJ, Ogea JL, Otero R, Paul HE, Pedrajas JM, Peris ML, Quezada CA, Riera-Mestre A, Rivas A, Rodríguez-Dávila MA, Román P, Rosa V, Ruiz J, Ruiz-Gamietea A, Ruiz-Giménez N, Sahuquillo JC, Samperiz A, Sánchez Muñoz-Torrero JF, Soler S, Tiberio G, Tolosa C,Trujillo J, Uresandi F, Valdés M, Valero B, Valle R, Vela J, Vidal G, Villalobos A, Villalta J, CZECH REPUBLIC: Malý R, Hirmerova J, ECUADOR: Salgado E, Sánchez GT, FRANCE: Bertoletti L, Bura-Riviere A, Farge-Bancel D, Mahe I, Merah A, Quere I, GERMANY: Schellong S, GREECE: Babalis D, Papadakis M, Tzinieris I. ISRAEL: Braester A, Brenner B, Tzoran I ITALY: Barillari G, Ciammaichella M, Di Micco P, Duce R, Maida R, Pasca S, Pesavento R, Piovaccari G, Piovella C, Poggio R, Prandoni P, Quintavalla R, Rota L, Schenone A, Tiraferri E, Tonello D, Tufano A, Visonà A, Zalunardo B, PORTUGAL: Barbosa AL, Gomes D, Gonçalves F, Santos M, Saraiva M, REPUBLIC OF MACEDONIA: Bosevski M, SWITZERLAND: Alatri A, Aujeski D, Bounameaux H, Calanca L, Mazzolai L.

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