Intern Emerg Med DOI 10.1007/s11739-014-1073-8
IM - ORIGINAL
Comparison of four scores to predict major bleeding in patients receiving anticoagulation for venous thromboembolism: findings from the RIETE registry Chiara Piovella • Fabio Dalla Valle • Javier Trujillo-Santos • Raffaele Pesavento • Leonor Lo´pez • Llorenc¸ Font • Reina Valle • Dolores Nauffal • Manuel Monreal • Paolo Prandoni • And the RIETE Investigators
Received: 26 November 2013 / Accepted: 17 April 2014 Ó SIMI 2014
Abstract Stratification of the individual bleeding risk prior to initiation of anticoagulation in patients with acute venous thromboembolism (VTE) has the potential to assist clinicians in making decisions about the proper intensity and duration of antithrombotic therapy. It is unclear which of the validated and internationally accepted scores recommended for the achievement of this important task has the best predictive value. We compared the predictive value of four validated scores (by Landefeld, Beyth, Kuijer and Ruiz-Gimenez, respectively) for the development of major bleeding complications occurring in the first 3 months in patients with acute VTE treated with conventional anticoagulation. Based on the population of RIETE Registry (international registry of patients with acute VTE), we identified those patients presenting all the required prognostic variables, and then calculated the ability of each score for predicting the bleeding risk. Of
40,265 eligible patients, we identified 8,717 meeting the recruitment criteria. Overall, 0.9 % of patients experienced at least one episode of major bleeding within 90 days of the index event. The proportion of patients classified as having a low risk varied between 1.2 and 3.7 %, that of patients having an intermediate risk between 76 and 93 %, and that of patients classified as having a high risk between 6.1 and 18 %. The area under the receiver operating characteristic ranged between 0.55 and 0.60, the positive predictive value between 1.5 and 3.2, and the likelihood ratio between 0.72 and 1.59. In conclusion, all four scores show a very low ability to predict the bleeding risk in patients with acute VTE undergoing conventional anticoagulation. Keywords Anticoagulation Bleeding Prediction Venous thromboembolism
A full list of RIETE investigators is given in the appendix. C. Piovella F. Dalla Valle R. Pesavento P. Prandoni (&) Vascular medicine unit, Department of Medicine, Clinica Medica 2, University of Padua, Via Giustiniani 2, 35128 Padua, Italy e-mail: [email protected] J. Trujillo-Santos Department of Internal Medicine, Hospital General Universitario Santa Lucı´a, Murcia, Spain L. Lo´pez Department of Internal Medicine, Hospital de Can Misses, Ibiza, Spain
R. Valle Department of Internal Medicine, Hospital Sierrallana, Cantabria, Spain D. Nauffal Department of Pneumonology, Hospital Universitario La Fe, Valencia, Spain M. Monreal Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
L. Font Department of Haematology, Hospital de Tortosa Verge de la Cinta, Tarragona, Spain
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Introduction The indications for anticoagulation therapy for primary and secondary prevention of thromboembolic complications in a variety of clinical conditions, such as venous thromboembolism (VTE), atrial fibrillation, prosthetic heart valves and myocardial infarction are based on well-established evidence, confirmed by several trials [1–5]. Unfortunately, however, the achievement of the required anticoagulant effect is often complicated by the development of major bleeding events. The incidence of bleeding associated with initial and long-term therapeutic doses of heparins and vitamin K antagonists (VKA) is about 10–17 % per year for all events, 2–5 % per year for major bleeding, and 0.5–1 % per year for fatal bleeding [6]. The reported annual occurrence of intracranial haemorrhage, which represents the most feared bleeding complication because of its high disability and fatality rate, is in the range of 0.2–0.4 % [7– 10]. Several parameters, including individual characteristics (age, gender, comorbidities), intensity and duration of anticoagulant therapy, and use of concomitant medications, have consistently been found to increase the risk of bleeding [11–14]. To estimate the hemorrhagic risk and to identify those patients who might develop major bleeding complications during anticoagulation therapy is a top priority. Aimed at assisting clinicians in the estimation of the individual bleeding risk prior to initiation of anticoagulation, a number of clinical prognostic score have been developed with variable grades of complexity and reproducibility. Whether and to what extent these scores can accurately identify individuals who are at a higher risk of bleeding is still a matter of debate. We decided to assess the comparative value of four internationally accepted and validated clinical scores (i.e., the scores by Landefeld, Beyth, Ruiz-Jimenez and Kuijer) [15–18] in predicting the bleeding risk in a real-life population such as that of the RIETE registry, an international registry of patients with acute VTE who were managed with conventional anticoagulation for at least 3 months. To this purpose, we identified the subgroup of patients belonging to the RIETE registry where all the prognostic variables required for the determination of each of the four bleeding scores had been recorded.
presenting with symptomatic venous thromboembolism (deep vein thrombosis (DVT), pulmonary embolism (PE), or both) confirmed by objective tests. Patients are excluded if they are currently participating in a therapeutic clinical trial with a blind medication, or if they would not be available for a 3-month follow-up. Enrolled patients are managed according to the clinical practice of each participating hospital, and are not subject to any predetermined intervention. After VTE diagnosis, all patients are followed up for at least 3 months. During each visit, any signs or symptoms suggesting VTE recurrences or bleeding complications are recorded. Each episode of clinically suspected recurrent DVT or PE has to be documented by compression ultrasonography, venography, lung scanning, helical CT scan or pulmonary angiography. Each patient provides written or oral consent for participation in the registry, according to the requirements of the ethics committee within each hospital. Study outcomes The major outcome for this study was the ability to distinguish between patients at low, mild or high risk of experiencing major bleeding during the first 90 days of anticoagulant therapy. Bleeding was defined as major if it was clinically overt and associated with a need for transfusion of two units or more of red blood cells, if it was retroperitoneal or intracranial, if it warranted permanent discontinuation of treatment, or it was fatal. Final classification was based on the full consensus of this committee. Study variables and definitions The following parameters are recorded in the RIETE registry: patient’s baseline characteristics; clinical status including any coexisting or underlying conditions; clinical characteristics of the VTE; risk factors; the treatment received upon VTE diagnosis; and outcome. The aetiology of VTE is defined as provoked (recent surgery, immobility, cancer, estrogens use, pregnancy, post-partum state, recent travel, or leg varicosities) or unprovoked. Surgical patients are defined as those who have undergone an operation in the 2 months prior to VTE diagnosis. Active cancer is defined as newly diagnosed cancer, metastatic cancer or cancer that is being treated. Data collection and monitoring
Methods Study design and setting The RIETE registry is an ongoing, international, multicenter, prospective cohort of consecutive patients
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The attending physicians ensure that eligible patients are consecutively enrolled. Data are recorded onto a computerbased case report form at each participating hospital and submitted to a centralized coordinating centre through a secure website. Encryption of data is used to enhance
Intern Emerg Med Table 1 Univariate analysis of the risk for major bleeding in 8,717 patients with acute VTE Major bleeding
Table 2 Treatment strategies and outcomes Major bleeding
No major bleeding Patients, N
Patients, N
82
8,494
Clinical characteristics
82
No major bleeding 8,494
Initial therapy LMWH
76 (93 %)
Gender (females) Mean age (years ± SD)
44 (54 %) 74 ± 14à
4,443 (52 %) 66 ± 18
Mean LMWH dose (IU/kg/day)
174 ± 39
179 ± 38
Unfractioned heparin
3 (3.7 %)
500 (5.9 %)
Inpatients
21 (26 %)
2,256 (27 %)
Mean UFH dose (IU/kg/day)
465 ± 86
342 ± 122
14 (17 %)
1,255 (15 %)
Thrombolytics* Inferior vena cava filterà
1 (1.2 %) 5 (6.1 %)
57 (0.7 %) 115 (1.4 %) 2,026 (24 %)
Underlying conditions Chronic lung disease
7,615 (90 %)
Chronic heart failure
16 (20 %)
728 (8.6 %)
Diabetes mellitus
15 (18 %)
1,293 (15 %)
LMWHà
44 (60 %)
Prior stroke
12 (15 %)
669 (7.9 %)
Mean LMWH dose (IU/kg/day)
135 ± 49
Prior myocardial infarction
11 (13 %)
746 (8.8 %)
Atrial fibrillation
9 (11 %)
599 (7.1 %)
Creatinine levels [1.2 mg/dLà
33 (40 %)
1,574 (19 %)
Fatal bleeding*
20 (24 %)
–
Anemiaà
45 (55 %)
28,284 (33 %)
33 (40 %)
–
Hematocrit \30 %à
12 (15 %)
600 (7.1 %)
Overall death (up to 10 days after major bleeding)*
Recent major bleeding
4 (4.9 %)
182 (2.1 %)
LMWH low-molecular-weight heparin, IU international units
Antiplatelet treatment
17 (21 %)
1,393 (17 %)
Differences between patients with- vs. without major bleeding: * P \ 0.05; à P \ 0.001
10 (12 %)
865 (10 %)
Risk factors Postoperative Immobility C4 days
30 (37 %)
2,032 (24 %)
Cancerà
22 (27 %)
1,785 (21 %)
Prior VTE
15 (18 %)
1,363 (16 %)
62 (76 %)
6,431 (76 %)
Initial VTE presentation Clinically overt PE
SD standard deviation, VTE venous thromboembolism, PE pulmonary embolism Differences between patients with- vs. without major bleeding: P \ 0.01; à P \ 0.001
confidentiality and security. Data quality is regularly monitored and documented electronically to detect inconsistencies or errors, which are resolved by the local coordinators. Data quality is also monitored by periodic visits to participating hospitals, by contract research organizations, who compare the medical records with the data in the web. A data audit is performed at periodic intervals. Patient identities remain confidential because they are identified by a unique number assigned by the study coordinating centre, which is responsible for all data management.
Long-term treatment
Vitamin K antagonists
à
29 (41 %)
142 ± 48 6,120 (74 %)
Outcome
intermediate, and high-risk patients and the 90-day major bleeding rate within each category for each score. To determine the accuracy of each score to predict a first major bleeding at 90 days, we estimated sensitivity, specificity, and positive and negative predictive values and likelihood ratios. Because we were specifically interested in individuals who would be at high risk of bleeding, we dichotomized patients as low and intermediate versus high risk. We assessed the discriminative power of each score to predict a first major bleeding at 90 days by calculating the area under the receiver operating characteristic (ROC) curve, performing a non-parametric test of the equality of the areas under the four ROC curves. We determined the goodness-of-fit of the score points for each score in a logistic regression model using the Pearson Chi square test. Weighted kappa index was calculated to determine the concordance between each two risk scales with three categories. All analyses were done using a commercial software package (SPSS 13.5, SPSS Inc., and Chicago, IL, USA).
Data analysis
Results
We compared baseline characteristics of patients with and without a first major bleeding using Chi square tests for categorical variables and nonparametric rank tests for continuous variables. We described the proportion of low,
Study patients Of 40,265 patients enrolled in the RIETE Registry at the time of our analysis, we identified 8,717 patients (21.6 %
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of RIETE population) of whom we had all the variables requested for each score we used. Half of the patients were male, the mean age was approximately 70 years, and about a quarter of the patients had primary pulmonary embolism. In the univariate analysis, age [74 years, cancer, recent (\30 days before) major bleeding, creatinine levels [1.2 mg/dl, anaemia and a haematocrit \30 % were associated with an increased risk of major bleeding (Table 1). Bleeding complications Overall, 82 patients (1 %) experienced a first major bleeding within 90 days of the index VTE event. Bleeding was fatal in 20 cases (24 %). Thirty-three of these 82 patients (40 %) who experienced a major bleeding died within 90 days (Table 2). The proportion of patients classified as high risk varied from 6.1 % for the Kuijer to 18 % for the Ruiz-Jimenez score (Table 3). Comparison of predictive accuracy and discriminatory power of the bleeding scores When dichotomized as high versus intermediate and low risk, the four scores had low sensitivities (8.1–18.2 %), positive predictive values (1.5–3.2 %) and likelihood ratio for a positive test (1.37–2.73) for predicting major bleeding at 90 days (Table 4). Goodness-of-fit was adequate for each score. The areas under the ROC curve varied from a low 0.55 (95 % CI 0.50–0.60) for the Kuijer score to a moderate 0.60 (95 % CI 0.54–0.65) for the Beyth score, without any significant difference in the overall comparison (P = 0.21) (Table 4). Finally, the concordance between the scales of risk was low (weighted kappa index less than 0.40) except between the scales of Landefeld et al. and of Beyth et al. which was excellent (weighted kappa index = 0.87) (Table 5).
Discussion Our prospective comparison showed that none of the four evaluated bleeding scores has an adequate accuracy and power to identify patients at high risk of short-term major bleeding. The Ruiz-Gimenez score has a slightly better positive predictive value (3.2 %) and positive likelihood ratio (2.73) than the other scores, but is still insufficient to identify a high-risk subgroup. The discriminative power of the four scores is poor to moderate at the best, with the areas under the ROC curve varying from 0.55 for the Kuijer to 0.60 for the Beyth score. Our results are fully consistent with those of recent prospective studies addressing the value of these and other less frequently used scores in
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Table 3 Prediction of major bleeding during anticoagulant treatment according to the different scores Scores
Number of patients
Number of major bleeding events (N = 82) (%)
Low risk
2,508
11 (3.4)
Intermediate risk
5,595
Landefeld et al.
High risk
62 (76)
614
9 (11)
Low risk
2,360
8 (9.8)
Intermediate risk
5,923
67 (82)
434
7 (8.5)
Low risk
1,153
1 (1.2)
Intermediate risk
6,897
76 (93)
667
5 (6.1)
720 7,142
3 (3.7) 64 (78)
855
15 (18)
Beyth et al.
High risk Kuijer et al.
High risk Ruiz-Gime´nez et al. Low risk Intermediate risk High risk
predicting the bleeding risk in cohorts of elderly individuals, where the rate of major bleeding (4–7 %) was higher than that (approximately 1 %) recorded in the RIETE registry, most likely as a result of different definitions for major bleeding and of the inclusion of elderly patients [19, 20]. Our study has important implications. Based on recent international guidelines, patients with the first episode of unprovoked VTE should be invited to extend anticoagulation far beyond the generally recommended 3-month period, provided they are at low risk of bleeding [21]. Failure to predict the bleeding risk with the use of the most commonly used hemorrhagic scores virtually precludes the identification of patients who could be candidates for indefinite anticoagulation. Therefore, it appears much more reasonable to identify patients in whom anticoagulation can be safely discontinued based on post-baseline features, such as residual vein thrombosis or D-dimer determination [22–24]. Indeed, currently available clinical bleeding risk scores have a limited accuracy and discriminative power in patients with VTE and cannot be recommended for routine use in clinical practice. A few limitations warrant proper comment. Essentially, we failed to test the value of other potentially meaningful scores [25, 26]. We accepted the classification of major bleeding as it was performed at the local participating centres in the absence of a central adjudication committee. The incidence of major bleeding observed in our cohort (1 %) was somewhat lower than that reported in the derivation studies by Kuijer and Ruiz-Gimenez (2.3 and 3.7 %, respectively) [17, 18], most likely because of slightly
Intern Emerg Med Table 4 Prognostic characteristics of the different scores Landefeld et al.
Beyth et al.
Kuijer et al.
Ruiz-Gime´nez et al.
Sensitivity % (95 % CI)
10.8 (5.8–19.3)
8.1 (4.6–13.9)
10.2 (7.8–13.3)
18.2 (14.9–21.9)
Specificity % (95 % CI)
93.0 (92.4–93.5)
95.4 (95.1–95.8)
92.5 (92.3–92.8)
93.4 (93.1–93.6)
PPV % (95 % CI)
1.5 (0.8–2.8)
1.7 (1.0–3.1)
1.6 (1.2–2.1)
3.2 (2.6–3.9)
NPV % (95 % CI)
99.1 (98.9–99.3)
99.0 (98.9–99.2)
98.9 (98.7–99.0)
98.9 (98.8–99.0)
Accuracy % (95 % CI)
92.2 (91.6–92.7)
94.6 (94.2–94.9)
91.6 (91.3–91.8)
92.5 (92.2–92.7)
LR?
1.54 (0.83–2.88)
1.77 (1.00–3.43)
1.37 (1.04–1.79)
2.73 (2.25–3.32)
LR-
0.96 (0.89–1.04)
0.96 (0.91–1.02)
0.97 (0.94–1.00)
0.88 (0.84–0.92)
AUC ROCa
0.59 (0.53–0.64)
0.60 (0.54–0.65)
0.55 (0.50–0.60)
0.56 (0.50–0.62)
AUC ROCb
0.52 (0.46–0.59)
0.52 (0.45–0.58)
0.49 (0.43–0.55)
0.54 (0.48–0.61)
CI confidence intervals, PPV positive predictive value, NPV negative positive value, LR likelihood ratio, AUC area under the curve, ROC receiver operating characteristic a
Comparison between high risk vs. intermediate or low risk
b
Comparison between high, intermediate and low risk
Table 5 Values of weighted kappa for the different scores
Landefeld et al.
Beyth et al.
Kuijer et al.
Ruiz-Gime´nez et al.
Landefeld et al.
–
–
–
–
Beyth et al.
0.87 (0.86–0.88)
–
–
–
Kuijer et al. Ruiz-Gime´nez et al.
0.36 (0.34–0.38)
0.36 (0.34–0.38)
–
–
0.32 (0.31–0.34)
0.30 (0.28–0.31)
0.27 (0.25–0.29)
–
different definitions of major bleeding, which could potentially account for differences in the prognostic performance. In conclusion, the bleeding risk scores we evaluated do not appear to be useful for targeting preventive interventions in patients receiving anticoagulants for VTE. As the bleeding risk stratification is an essential part of the management of anticoagulation, the identification of new prognostic scores that can accurately predict the risk of bleeding in VTE patients treated with anticoagulant drugs is warranted. Acknowledgments 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 19.8 % of the total patients included in the RIETE Registry. We also thank the RIETE Registry Coordinating Center, S & H Medical Science Service, for their quality control data, logistic and administrative support. Conflict of interest
None.
Appendix Coordinator of the RIETE Registry: Dr. Manuel Monreal (Spain). RIETE Steering Committee Members: Dr. Herve` 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 Maly´ (Czech Republic). RIETE Registry Coordinating Center: S and H Medical Science Service. Members of the RIETE Group: Spain: Adarraga MD, Arcelus JI, Ballaz A, Barba R, Barro´n M, Barro´n-Andre´s B, Bascun˜ana J, Blanco-Molina A, Bueso T, Casado I, Castejo´n N, Conget F, del Molino F, del Toro J, Falga´ C, Ferna´ndez-Capita´n C, Font L, Fuentes MI, Gallego P, Garcı´a-Bragado F, Garcı´a-Lorenzo MD, Go´mez V, Gonza´lez J, Gonza´lez-Bachs E, Grau E, Guil M, Gutie´rrez J, Herna´ndez L, Herna´ndez-Huerta S, Jaras MJ, Jime´nez D, Lecumberri R, Lobo JL, Lo´pez-Jime´nez L, Lo´pez-Montes L, Lo´pez-Reyes R, Lo´pez-Sa´ez JB, Lorente MA, Lorenzo A, Luque JM, Madridano O, Marchena PJ, Martı´n M, Monreal M, Nauffal D, Nieto JA, Nu´n˜ez MJ, Ogea JL, Pedrajas JM, Peris ML, Porras JA, Riera-Mestre A, Rivas A, Rodrı´guez-Da´vila MA, Roma´n P, Roncero A,
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Rosa V, Ruiz-Gime´nez N, Ruiz J, Sahuquillo JC, Samperiz A, Sa´nchez Mun˜oz-Torrero JF, Soler S, Surin˜ach JM, Tiberio G, Tolosa C, Trujillo-Santos J, Uresandi F, Valde´s M, Valero B, Valle R, Vela J, Vidal G, Villalta J, Belgium: Verhamme P, Peerlinck K, Brazil: Gadelha T, Ribeiro R, Vassalo J, Canada: Wells P, CZECH REPUBLIC: Maly´ R, Hirmerova J, Kaletova M, Tomko T, France: Bertoletti L, Bura-Riviere A, Farge-Bancel D, Hij A, Mahe I, Merah A, Germany: Schellong S, Greece: Babalis D, Papadakis M, Tzinieris I, ISRAEL: Braester A, Brenner B, Tzoran I, Zeltser D, Italy: Amitrano M, Barillari G, Ciammaichella M, Di Micco P, Duce R, Giorgi-Pierfranceschi M, Maida R, Prandoni P, Quintavalla R, Rocci A, Rota L, Tiraferri E, Tonello D, Tufano A, Visona` A, Zalunardo B, Portugal: Sa´ Bastos M, Sousa MS, Rei R, Republic of Macedonia: Bosevski M, Kovacevic D, Switzerland: Bounameaux H, Mazzolai L.
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11. Arcelus JI, Monreal M, Caprini JA et al (2008) Clinical presentation and time-course of postoperative venous thromboembolism: results from the RIETE Registry. Thromb Haemost 99:546–551 12. Munoz FJ, Mismetti P, Poggio R et al (2008) Clinical outcome of patients with upper-extremity deep vein thrombosis: results from the RIETE Registry. Chest 133:143–148 13. Trujillo-Santos J, Prandoni P et al (2008) Clinical outcome in patients with venous thromboembolism and hidden cancer. Findings from the RIETE Registry. J Thromb Haemost 6:251–255 14. Laporte S, Mismetti P, Decousus H et al (2008) 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. Circulation 117:1711–1716 15. Landefeld CS, Goldman L (1989) Major bleeding in out-patients treated with warfarin:incidence and prediction by factors known at the start of outpatient therapy. Am J Med 87:144–152 16. Beyth RJ, Quinn LM, Landefeld CS (1998) Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 105:91–99 17. Kuijer PM, Hutten BA, Prins MH, Buller HR (1999) Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 159:457–460 18. Ruiz-Gimenez N, Suarez C, Gonzalez R et al (2008) Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 100:26–31 19. Scherz N, Me´an M, Limacher A et al (2013) Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost 11:435–443 20. Donze´ J, Rodondi N, Waeber G, Monney P, Cornuz J, Aujesky D (2012) Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. Am J Med 125:1095–1102 21. Kearon C, Akl EA, Comerota AJ et al (2012) Antithrombotic therapy for VTE disease. In: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2 Suppl):419–494 22. Prandoni P, Prins MH, Lensing AWA et al (2009) Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 150:577–585 23. Palareti G, Cosmi B, Legnani C et al (2006) D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 355:1780–1789 24. Palareti G, Cosmi B, Legnani C, et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism; a management study. Blood 2014 [epub ahead of print] 25. Wells PS, Forgie MA, Simms M et al (2003) The outpatient bleeding risk index: validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med 163:917–920 26. Aspinall SL, DeSanzo BE, Trilli LE et al (2005) Bleeding risk index in an anticoagulation clinic. Assessment by indication and implications for care. J Gen Intern Med 20:1008–1013
IM - ORIGINAL
Comparison of four scores to predict major bleeding in patients receiving anticoagulation for venous thromboembolism: findings from the RIETE registry Chiara Piovella • Fabio Dalla Valle • Javier Trujillo-Santos • Raffaele Pesavento • Leonor Lo´pez • Llorenc¸ Font • Reina Valle • Dolores Nauffal • Manuel Monreal • Paolo Prandoni • And the RIETE Investigators
Received: 26 November 2013 / Accepted: 17 April 2014 Ó SIMI 2014
Abstract Stratification of the individual bleeding risk prior to initiation of anticoagulation in patients with acute venous thromboembolism (VTE) has the potential to assist clinicians in making decisions about the proper intensity and duration of antithrombotic therapy. It is unclear which of the validated and internationally accepted scores recommended for the achievement of this important task has the best predictive value. We compared the predictive value of four validated scores (by Landefeld, Beyth, Kuijer and Ruiz-Gimenez, respectively) for the development of major bleeding complications occurring in the first 3 months in patients with acute VTE treated with conventional anticoagulation. Based on the population of RIETE Registry (international registry of patients with acute VTE), we identified those patients presenting all the required prognostic variables, and then calculated the ability of each score for predicting the bleeding risk. Of
40,265 eligible patients, we identified 8,717 meeting the recruitment criteria. Overall, 0.9 % of patients experienced at least one episode of major bleeding within 90 days of the index event. The proportion of patients classified as having a low risk varied between 1.2 and 3.7 %, that of patients having an intermediate risk between 76 and 93 %, and that of patients classified as having a high risk between 6.1 and 18 %. The area under the receiver operating characteristic ranged between 0.55 and 0.60, the positive predictive value between 1.5 and 3.2, and the likelihood ratio between 0.72 and 1.59. In conclusion, all four scores show a very low ability to predict the bleeding risk in patients with acute VTE undergoing conventional anticoagulation. Keywords Anticoagulation Bleeding Prediction Venous thromboembolism
A full list of RIETE investigators is given in the appendix. C. Piovella F. Dalla Valle R. Pesavento P. Prandoni (&) Vascular medicine unit, Department of Medicine, Clinica Medica 2, University of Padua, Via Giustiniani 2, 35128 Padua, Italy e-mail: [email protected] J. Trujillo-Santos Department of Internal Medicine, Hospital General Universitario Santa Lucı´a, Murcia, Spain L. Lo´pez Department of Internal Medicine, Hospital de Can Misses, Ibiza, Spain
R. Valle Department of Internal Medicine, Hospital Sierrallana, Cantabria, Spain D. Nauffal Department of Pneumonology, Hospital Universitario La Fe, Valencia, Spain M. Monreal Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
L. Font Department of Haematology, Hospital de Tortosa Verge de la Cinta, Tarragona, Spain
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Introduction The indications for anticoagulation therapy for primary and secondary prevention of thromboembolic complications in a variety of clinical conditions, such as venous thromboembolism (VTE), atrial fibrillation, prosthetic heart valves and myocardial infarction are based on well-established evidence, confirmed by several trials [1–5]. Unfortunately, however, the achievement of the required anticoagulant effect is often complicated by the development of major bleeding events. The incidence of bleeding associated with initial and long-term therapeutic doses of heparins and vitamin K antagonists (VKA) is about 10–17 % per year for all events, 2–5 % per year for major bleeding, and 0.5–1 % per year for fatal bleeding [6]. The reported annual occurrence of intracranial haemorrhage, which represents the most feared bleeding complication because of its high disability and fatality rate, is in the range of 0.2–0.4 % [7– 10]. Several parameters, including individual characteristics (age, gender, comorbidities), intensity and duration of anticoagulant therapy, and use of concomitant medications, have consistently been found to increase the risk of bleeding [11–14]. To estimate the hemorrhagic risk and to identify those patients who might develop major bleeding complications during anticoagulation therapy is a top priority. Aimed at assisting clinicians in the estimation of the individual bleeding risk prior to initiation of anticoagulation, a number of clinical prognostic score have been developed with variable grades of complexity and reproducibility. Whether and to what extent these scores can accurately identify individuals who are at a higher risk of bleeding is still a matter of debate. We decided to assess the comparative value of four internationally accepted and validated clinical scores (i.e., the scores by Landefeld, Beyth, Ruiz-Jimenez and Kuijer) [15–18] in predicting the bleeding risk in a real-life population such as that of the RIETE registry, an international registry of patients with acute VTE who were managed with conventional anticoagulation for at least 3 months. To this purpose, we identified the subgroup of patients belonging to the RIETE registry where all the prognostic variables required for the determination of each of the four bleeding scores had been recorded.
presenting with symptomatic venous thromboembolism (deep vein thrombosis (DVT), pulmonary embolism (PE), or both) confirmed by objective tests. Patients are excluded if they are currently participating in a therapeutic clinical trial with a blind medication, or if they would not be available for a 3-month follow-up. Enrolled patients are managed according to the clinical practice of each participating hospital, and are not subject to any predetermined intervention. After VTE diagnosis, all patients are followed up for at least 3 months. During each visit, any signs or symptoms suggesting VTE recurrences or bleeding complications are recorded. Each episode of clinically suspected recurrent DVT or PE has to be documented by compression ultrasonography, venography, lung scanning, helical CT scan or pulmonary angiography. Each patient provides written or oral consent for participation in the registry, according to the requirements of the ethics committee within each hospital. Study outcomes The major outcome for this study was the ability to distinguish between patients at low, mild or high risk of experiencing major bleeding during the first 90 days of anticoagulant therapy. Bleeding was defined as major if it was clinically overt and associated with a need for transfusion of two units or more of red blood cells, if it was retroperitoneal or intracranial, if it warranted permanent discontinuation of treatment, or it was fatal. Final classification was based on the full consensus of this committee. Study variables and definitions The following parameters are recorded in the RIETE registry: patient’s baseline characteristics; clinical status including any coexisting or underlying conditions; clinical characteristics of the VTE; risk factors; the treatment received upon VTE diagnosis; and outcome. The aetiology of VTE is defined as provoked (recent surgery, immobility, cancer, estrogens use, pregnancy, post-partum state, recent travel, or leg varicosities) or unprovoked. Surgical patients are defined as those who have undergone an operation in the 2 months prior to VTE diagnosis. Active cancer is defined as newly diagnosed cancer, metastatic cancer or cancer that is being treated. Data collection and monitoring
Methods Study design and setting The RIETE registry is an ongoing, international, multicenter, prospective cohort of consecutive patients
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The attending physicians ensure that eligible patients are consecutively enrolled. Data are recorded onto a computerbased case report form at each participating hospital and submitted to a centralized coordinating centre through a secure website. Encryption of data is used to enhance
Intern Emerg Med Table 1 Univariate analysis of the risk for major bleeding in 8,717 patients with acute VTE Major bleeding
Table 2 Treatment strategies and outcomes Major bleeding
No major bleeding Patients, N
Patients, N
82
8,494
Clinical characteristics
82
No major bleeding 8,494
Initial therapy LMWH
76 (93 %)
Gender (females) Mean age (years ± SD)
44 (54 %) 74 ± 14à
4,443 (52 %) 66 ± 18
Mean LMWH dose (IU/kg/day)
174 ± 39
179 ± 38
Unfractioned heparin
3 (3.7 %)
500 (5.9 %)
Inpatients
21 (26 %)
2,256 (27 %)
Mean UFH dose (IU/kg/day)
465 ± 86
342 ± 122
14 (17 %)
1,255 (15 %)
Thrombolytics* Inferior vena cava filterà
1 (1.2 %) 5 (6.1 %)
57 (0.7 %) 115 (1.4 %) 2,026 (24 %)
Underlying conditions Chronic lung disease
7,615 (90 %)
Chronic heart failure
16 (20 %)
728 (8.6 %)
Diabetes mellitus
15 (18 %)
1,293 (15 %)
LMWHà
44 (60 %)
Prior stroke
12 (15 %)
669 (7.9 %)
Mean LMWH dose (IU/kg/day)
135 ± 49
Prior myocardial infarction
11 (13 %)
746 (8.8 %)
Atrial fibrillation
9 (11 %)
599 (7.1 %)
Creatinine levels [1.2 mg/dLà
33 (40 %)
1,574 (19 %)
Fatal bleeding*
20 (24 %)
–
Anemiaà
45 (55 %)
28,284 (33 %)
33 (40 %)
–
Hematocrit \30 %à
12 (15 %)
600 (7.1 %)
Overall death (up to 10 days after major bleeding)*
Recent major bleeding
4 (4.9 %)
182 (2.1 %)
LMWH low-molecular-weight heparin, IU international units
Antiplatelet treatment
17 (21 %)
1,393 (17 %)
Differences between patients with- vs. without major bleeding: * P \ 0.05; à P \ 0.001
10 (12 %)
865 (10 %)
Risk factors Postoperative Immobility C4 days
30 (37 %)
2,032 (24 %)
Cancerà
22 (27 %)
1,785 (21 %)
Prior VTE
15 (18 %)
1,363 (16 %)
62 (76 %)
6,431 (76 %)
Initial VTE presentation Clinically overt PE
SD standard deviation, VTE venous thromboembolism, PE pulmonary embolism Differences between patients with- vs. without major bleeding: P \ 0.01; à P \ 0.001
confidentiality and security. Data quality is regularly monitored and documented electronically to detect inconsistencies or errors, which are resolved by the local coordinators. Data quality is also monitored by periodic visits to participating hospitals, by contract research organizations, who compare the medical records with the data in the web. A data audit is performed at periodic intervals. Patient identities remain confidential because they are identified by a unique number assigned by the study coordinating centre, which is responsible for all data management.
Long-term treatment
Vitamin K antagonists
à
29 (41 %)
142 ± 48 6,120 (74 %)
Outcome
intermediate, and high-risk patients and the 90-day major bleeding rate within each category for each score. To determine the accuracy of each score to predict a first major bleeding at 90 days, we estimated sensitivity, specificity, and positive and negative predictive values and likelihood ratios. Because we were specifically interested in individuals who would be at high risk of bleeding, we dichotomized patients as low and intermediate versus high risk. We assessed the discriminative power of each score to predict a first major bleeding at 90 days by calculating the area under the receiver operating characteristic (ROC) curve, performing a non-parametric test of the equality of the areas under the four ROC curves. We determined the goodness-of-fit of the score points for each score in a logistic regression model using the Pearson Chi square test. Weighted kappa index was calculated to determine the concordance between each two risk scales with three categories. All analyses were done using a commercial software package (SPSS 13.5, SPSS Inc., and Chicago, IL, USA).
Data analysis
Results
We compared baseline characteristics of patients with and without a first major bleeding using Chi square tests for categorical variables and nonparametric rank tests for continuous variables. We described the proportion of low,
Study patients Of 40,265 patients enrolled in the RIETE Registry at the time of our analysis, we identified 8,717 patients (21.6 %
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of RIETE population) of whom we had all the variables requested for each score we used. Half of the patients were male, the mean age was approximately 70 years, and about a quarter of the patients had primary pulmonary embolism. In the univariate analysis, age [74 years, cancer, recent (\30 days before) major bleeding, creatinine levels [1.2 mg/dl, anaemia and a haematocrit \30 % were associated with an increased risk of major bleeding (Table 1). Bleeding complications Overall, 82 patients (1 %) experienced a first major bleeding within 90 days of the index VTE event. Bleeding was fatal in 20 cases (24 %). Thirty-three of these 82 patients (40 %) who experienced a major bleeding died within 90 days (Table 2). The proportion of patients classified as high risk varied from 6.1 % for the Kuijer to 18 % for the Ruiz-Jimenez score (Table 3). Comparison of predictive accuracy and discriminatory power of the bleeding scores When dichotomized as high versus intermediate and low risk, the four scores had low sensitivities (8.1–18.2 %), positive predictive values (1.5–3.2 %) and likelihood ratio for a positive test (1.37–2.73) for predicting major bleeding at 90 days (Table 4). Goodness-of-fit was adequate for each score. The areas under the ROC curve varied from a low 0.55 (95 % CI 0.50–0.60) for the Kuijer score to a moderate 0.60 (95 % CI 0.54–0.65) for the Beyth score, without any significant difference in the overall comparison (P = 0.21) (Table 4). Finally, the concordance between the scales of risk was low (weighted kappa index less than 0.40) except between the scales of Landefeld et al. and of Beyth et al. which was excellent (weighted kappa index = 0.87) (Table 5).
Discussion Our prospective comparison showed that none of the four evaluated bleeding scores has an adequate accuracy and power to identify patients at high risk of short-term major bleeding. The Ruiz-Gimenez score has a slightly better positive predictive value (3.2 %) and positive likelihood ratio (2.73) than the other scores, but is still insufficient to identify a high-risk subgroup. The discriminative power of the four scores is poor to moderate at the best, with the areas under the ROC curve varying from 0.55 for the Kuijer to 0.60 for the Beyth score. Our results are fully consistent with those of recent prospective studies addressing the value of these and other less frequently used scores in
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Table 3 Prediction of major bleeding during anticoagulant treatment according to the different scores Scores
Number of patients
Number of major bleeding events (N = 82) (%)
Low risk
2,508
11 (3.4)
Intermediate risk
5,595
Landefeld et al.
High risk
62 (76)
614
9 (11)
Low risk
2,360
8 (9.8)
Intermediate risk
5,923
67 (82)
434
7 (8.5)
Low risk
1,153
1 (1.2)
Intermediate risk
6,897
76 (93)
667
5 (6.1)
720 7,142
3 (3.7) 64 (78)
855
15 (18)
Beyth et al.
High risk Kuijer et al.
High risk Ruiz-Gime´nez et al. Low risk Intermediate risk High risk
predicting the bleeding risk in cohorts of elderly individuals, where the rate of major bleeding (4–7 %) was higher than that (approximately 1 %) recorded in the RIETE registry, most likely as a result of different definitions for major bleeding and of the inclusion of elderly patients [19, 20]. Our study has important implications. Based on recent international guidelines, patients with the first episode of unprovoked VTE should be invited to extend anticoagulation far beyond the generally recommended 3-month period, provided they are at low risk of bleeding [21]. Failure to predict the bleeding risk with the use of the most commonly used hemorrhagic scores virtually precludes the identification of patients who could be candidates for indefinite anticoagulation. Therefore, it appears much more reasonable to identify patients in whom anticoagulation can be safely discontinued based on post-baseline features, such as residual vein thrombosis or D-dimer determination [22–24]. Indeed, currently available clinical bleeding risk scores have a limited accuracy and discriminative power in patients with VTE and cannot be recommended for routine use in clinical practice. A few limitations warrant proper comment. Essentially, we failed to test the value of other potentially meaningful scores [25, 26]. We accepted the classification of major bleeding as it was performed at the local participating centres in the absence of a central adjudication committee. The incidence of major bleeding observed in our cohort (1 %) was somewhat lower than that reported in the derivation studies by Kuijer and Ruiz-Gimenez (2.3 and 3.7 %, respectively) [17, 18], most likely because of slightly
Intern Emerg Med Table 4 Prognostic characteristics of the different scores Landefeld et al.
Beyth et al.
Kuijer et al.
Ruiz-Gime´nez et al.
Sensitivity % (95 % CI)
10.8 (5.8–19.3)
8.1 (4.6–13.9)
10.2 (7.8–13.3)
18.2 (14.9–21.9)
Specificity % (95 % CI)
93.0 (92.4–93.5)
95.4 (95.1–95.8)
92.5 (92.3–92.8)
93.4 (93.1–93.6)
PPV % (95 % CI)
1.5 (0.8–2.8)
1.7 (1.0–3.1)
1.6 (1.2–2.1)
3.2 (2.6–3.9)
NPV % (95 % CI)
99.1 (98.9–99.3)
99.0 (98.9–99.2)
98.9 (98.7–99.0)
98.9 (98.8–99.0)
Accuracy % (95 % CI)
92.2 (91.6–92.7)
94.6 (94.2–94.9)
91.6 (91.3–91.8)
92.5 (92.2–92.7)
LR?
1.54 (0.83–2.88)
1.77 (1.00–3.43)
1.37 (1.04–1.79)
2.73 (2.25–3.32)
LR-
0.96 (0.89–1.04)
0.96 (0.91–1.02)
0.97 (0.94–1.00)
0.88 (0.84–0.92)
AUC ROCa
0.59 (0.53–0.64)
0.60 (0.54–0.65)
0.55 (0.50–0.60)
0.56 (0.50–0.62)
AUC ROCb
0.52 (0.46–0.59)
0.52 (0.45–0.58)
0.49 (0.43–0.55)
0.54 (0.48–0.61)
CI confidence intervals, PPV positive predictive value, NPV negative positive value, LR likelihood ratio, AUC area under the curve, ROC receiver operating characteristic a
Comparison between high risk vs. intermediate or low risk
b
Comparison between high, intermediate and low risk
Table 5 Values of weighted kappa for the different scores
Landefeld et al.
Beyth et al.
Kuijer et al.
Ruiz-Gime´nez et al.
Landefeld et al.
–
–
–
–
Beyth et al.
0.87 (0.86–0.88)
–
–
–
Kuijer et al. Ruiz-Gime´nez et al.
0.36 (0.34–0.38)
0.36 (0.34–0.38)
–
–
0.32 (0.31–0.34)
0.30 (0.28–0.31)
0.27 (0.25–0.29)
–
different definitions of major bleeding, which could potentially account for differences in the prognostic performance. In conclusion, the bleeding risk scores we evaluated do not appear to be useful for targeting preventive interventions in patients receiving anticoagulants for VTE. As the bleeding risk stratification is an essential part of the management of anticoagulation, the identification of new prognostic scores that can accurately predict the risk of bleeding in VTE patients treated with anticoagulant drugs is warranted. Acknowledgments 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 19.8 % of the total patients included in the RIETE Registry. We also thank the RIETE Registry Coordinating Center, S & H Medical Science Service, for their quality control data, logistic and administrative support. Conflict of interest
None.
Appendix Coordinator of the RIETE Registry: Dr. Manuel Monreal (Spain). RIETE Steering Committee Members: Dr. Herve` 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 Maly´ (Czech Republic). RIETE Registry Coordinating Center: S and H Medical Science Service. Members of the RIETE Group: Spain: Adarraga MD, Arcelus JI, Ballaz A, Barba R, Barro´n M, Barro´n-Andre´s B, Bascun˜ana J, Blanco-Molina A, Bueso T, Casado I, Castejo´n N, Conget F, del Molino F, del Toro J, Falga´ C, Ferna´ndez-Capita´n C, Font L, Fuentes MI, Gallego P, Garcı´a-Bragado F, Garcı´a-Lorenzo MD, Go´mez V, Gonza´lez J, Gonza´lez-Bachs E, Grau E, Guil M, Gutie´rrez J, Herna´ndez L, Herna´ndez-Huerta S, Jaras MJ, Jime´nez D, Lecumberri R, Lobo JL, Lo´pez-Jime´nez L, Lo´pez-Montes L, Lo´pez-Reyes R, Lo´pez-Sa´ez JB, Lorente MA, Lorenzo A, Luque JM, Madridano O, Marchena PJ, Martı´n M, Monreal M, Nauffal D, Nieto JA, Nu´n˜ez MJ, Ogea JL, Pedrajas JM, Peris ML, Porras JA, Riera-Mestre A, Rivas A, Rodrı´guez-Da´vila MA, Roma´n P, Roncero A,
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Rosa V, Ruiz-Gime´nez N, Ruiz J, Sahuquillo JC, Samperiz A, Sa´nchez Mun˜oz-Torrero JF, Soler S, Surin˜ach JM, Tiberio G, Tolosa C, Trujillo-Santos J, Uresandi F, Valde´s M, Valero B, Valle R, Vela J, Vidal G, Villalta J, Belgium: Verhamme P, Peerlinck K, Brazil: Gadelha T, Ribeiro R, Vassalo J, Canada: Wells P, CZECH REPUBLIC: Maly´ R, Hirmerova J, Kaletova M, Tomko T, France: Bertoletti L, Bura-Riviere A, Farge-Bancel D, Hij A, Mahe I, Merah A, Germany: Schellong S, Greece: Babalis D, Papadakis M, Tzinieris I, ISRAEL: Braester A, Brenner B, Tzoran I, Zeltser D, Italy: Amitrano M, Barillari G, Ciammaichella M, Di Micco P, Duce R, Giorgi-Pierfranceschi M, Maida R, Prandoni P, Quintavalla R, Rocci A, Rota L, Tiraferri E, Tonello D, Tufano A, Visona` A, Zalunardo B, Portugal: Sa´ Bastos M, Sousa MS, Rei R, Republic of Macedonia: Bosevski M, Kovacevic D, Switzerland: Bounameaux H, Mazzolai L.
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