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External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis
EJINME-03311; No of Pages 2 European Journal of Internal Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis Keywords: Cancer-associated venous thrombosis Recurrence risk Prediction rule
Dear Editor, Venous thromboembolism (VTE) and cancer are two major public health issues that are closely linked. Cancer is part of the major risk factors for VTE and it is estimated that up to 20% of cancer patients will face a VTE issue during the course of their malignancy [1,2]. Patients who develop VTE during the course of their malignancy are at high risk for VTE recurrence: 10 to 17% of them will experience a new VTE event within the first six months of anticoagulation [3]. However, this risk varies depending on several parameters such as cancer site, cancer histology, or cancer stage [4]. The modified Ottawa score is a clinical prediction rule that stratifies the risk for VTE recurrence in patients with cancer-associated VTE by using simple predictors [5]. Each of female sex, lung cancer, and prior history of VTE give 1 point and each of breast cancer and cancer stage I + II give a negative point. The sum of the points classifies patients into low (score ≤ − 1), intermediate (score = 0) or high risk (score ≥ 1) of recurrent VTE during the first six months of anticoagulation with recurrence rates of 5.1%, 9.8%, and 13.9% respectively [5]. However, external validation of the Ottawa score has been inconsistent when applied in different cohorts of cancer patients [6,7]. In this study, we assessed whether the modified Ottawa score could accurately stratify the risk for VTE recurrence in an independent dataset. Since May 2000, we have asked to participate in a VTE cohort all consecutive patients aged 18 years or more seen at the outpatient clinic or admitted to Brest University Hospital for symptomatic deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE). For this analysis, we applied the modified Ottawa score in patients who were included in the cohort for a proximal symptomatic cancerassociated DVT of the lower limbs or symptomatic cancer-associated PE and no surgery in the preceding 3 months. Because we did not record exact cancer stage, we attributed a negative point for “absence of metastasis” instead of for “cancer stages I + II”. The primary end point of the study was recurrence of symptomatic VTE. The cumulative risk for VTE recurrence was estimated by using the Kaplan–Meier method. The study protocol was approved by our hospital scientific and ethics board. All patients gave informed consent. Between May 2000 and July 2010, 235 patients with cancerassociated VTE were included in the study. Of these, 79 patients were excluded due to recent cancer surgery (n = 45), isolated distal DVT (n = 29) or no follow-up (n = 14). Mean age of the 156 studied patients
was 69.5 ± 1.8 years, and 70 (44.9%) were female. There were 23 patients with lung cancer (14.7%), 17 with breast cancer (10.9%), 36 with past history of VTE (23.1%), and 94 without metastasis (60.2%). Fourteen patients had a recurrent VTE event during follow-up corresponding to an estimated 6-months cumulative recurrence rate of 11.9% (95% CI 7.2–19.4). When the modified Ottawa score was applied to our sample, 43 patients (27.6%) were classified at low risk for VTE recurrence, 62 (39.7%) at intermediate risk, and 51 (32.7%) at high risk (Table 1). The 6-month cumulative recurrence rate of VTE was 2.6% (95% CI 0.4–17.2) in low-risk patients (1 recurrence), 8.6% (95% CI 3.3–21.6) in intermediate-risk patients (4 recurrences), and 24.9% (95% CI 13.5– 43.1) in high-risk patients (9 recurrences) (p = 0.02 by log-rank test) (Fig. 1). In our dataset, the modified Ottawa score could categorize our patients into 3 groups at different risks for recurrent VTE. In particular, the model clearly identified low-risk and high-risk patients, with a 22% absolute difference in the risk for recurrent VTE between low-risk group and high-risk group. Two main points should be discussed. Firstly, the recurrence rate of VTE that we observed in the high-risk group (24.9%) was particularly high compared to the rate found in the original validation cohort (13.9%) [5]. Our patients were probably more severe than those included in the original validation cohort that was based on two randomized trials whose inclusion criteria enclosed extended life expectancy. Nevertheless, the overall recurrence rate observed in our patients is consistent with previous studies [3]. Secondly, by attributing a negative point to all patients without metastasis instead of cancer stage I + II as originally set in the derivation and validation studies, we may have missed patients who should have been classified into the intermediate risk group. However, when the predictor “cancer stage I + II” was also replaced by “absence of metastasis” in an independent Dutch cohort of 416 patients, the modified Ottawa score was still reproducible and offered an accurate estimation for the risk of recurrent VTE in cancer patients [7]. Cancer staging is not easy from a nononcologist assessment; therefore, giving a negative point to patients without metastasis would be the easiest way to accurately classify patients. In conclusion, our data bring out further evidence suggesting that the modified Ottawa score can identify patients at low or high risk for recurrence after a cancer-associated VTE event, using “no metastasis” as predictor instead of “cancer stage I + II”. If other external validation studies demonstrate that the absence of metastases clearly helps to stratify patients into a lower risk for recurrent VTE, the Ottawa score will certainly be implemented in order to tailor anticoagulation therapy in patients with cancer-associated VTE.
Conflict of interests To the best of our knowledge, no conflict of interest, financial or other, exists.
http://dx.doi.org/10.1016/j.ejim.2016.08.001 0953-6205/© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Astruc N, et al, External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.001
e2
Letter to the Editor
Table 1 Number of patients and number of VTE recurrences and deaths according to the sum of points obtained by applying the modified Ottawa score. Sum of points
Recurrence risk
Number of patients
Recurrent VTE N (%)
−1 0 1 2 3
Low Intermediate High
43 (27.6%) 62 (39.7%) 43 (27.6%) 5 (3.2%) 3 (1.9%)
1 (2.3%) 4 (6.45%) 6 (13.9%) 2 (40.0%) 1 (33.3%)
VTE: venous thromboembolism.
[2] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160(6):809–15. [3] Carrier M, Cameron C, Delluc A, Castellucci L, Khorana AA, Lee AY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res 2014;134(6):1214–9. [4] Louzada ML, Majeed H, Dao V, Wells PS. Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies. Blood Coagul Fibrinolysis 2011;22(2):86–91. [5] Louzada ML, Carrier M, Lazo-Langner A, Dao V, Kovacs MJ, Ramsay TO, et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation 2012;126(4):448–54. [6] Ahn S, Lim KS, Lee YS, Lee JL. Validation of the clinical prediction rule for recurrent venous thromboembolism in cancer patients: the Ottawa score. Support Care Cancer 2013;21(8):2309–13. [7] den Exter PL, Kooiman J, Huisman MV. Validation of the Ottawa prognostic score for the prediction of recurrent venous thromboembolism in patients with cancerassociated thrombosis. J Thromb Haemost 2013;11(5):998–1000.
Nolwenn Astruc Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest F-29609, France Jean-Christophe Ianotto Oncology & Haematology Institute, Brest University Hospital, Brest F-29609, France Brest University (Université de Bretagne Occidentale), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Equipe d'Accueil 3878, Brest F-29609, France Jean-Philippe Metges Oncology & Haematology Institute, Brest University Hospital, Brest F-29609, France Fig. 1. Cumulative risk of recurrent venous thromboembolism according to risk category.
Acknowledgment The study was supported by grants from INSERM (Contrat de Recherche Stratégique 2001, CRES No. 4CR05G), from Région Bretagne (Programme 1044-04013235 no. 1440) and Programme Hospitalier de Recherche Clinique 2000. The Centre Hospitalier Régional et Universitaire de Brest promoted the study. The funders of this study had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.
References [1] Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166(4):458–64.
Karine Lacut Brest University (Université de Bretagne Occidentale), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Equipe d'Accueil 3878, Brest F-29609, France Centre d'Investigation Clinique INSERM 1412, Brest University Hospital, Brest F-29609, France Aurélien Delluc Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest F-29609, France Brest University (Université de Bretagne Occidentale), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Equipe d'Accueil 3878, Brest F-29609, France Corresponding author at: EA 3878, Département de Médecine interne et de pneumologie, Centre hospitalier universitaire de Brest, Hôpital de la Cavale Blanche, 29609, Brest Cedex, France. 29 July 2016 Available online xxxx
Please cite this article as: Astruc N, et al, External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.001
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis Keywords: Cancer-associated venous thrombosis Recurrence risk Prediction rule
Dear Editor, Venous thromboembolism (VTE) and cancer are two major public health issues that are closely linked. Cancer is part of the major risk factors for VTE and it is estimated that up to 20% of cancer patients will face a VTE issue during the course of their malignancy [1,2]. Patients who develop VTE during the course of their malignancy are at high risk for VTE recurrence: 10 to 17% of them will experience a new VTE event within the first six months of anticoagulation [3]. However, this risk varies depending on several parameters such as cancer site, cancer histology, or cancer stage [4]. The modified Ottawa score is a clinical prediction rule that stratifies the risk for VTE recurrence in patients with cancer-associated VTE by using simple predictors [5]. Each of female sex, lung cancer, and prior history of VTE give 1 point and each of breast cancer and cancer stage I + II give a negative point. The sum of the points classifies patients into low (score ≤ − 1), intermediate (score = 0) or high risk (score ≥ 1) of recurrent VTE during the first six months of anticoagulation with recurrence rates of 5.1%, 9.8%, and 13.9% respectively [5]. However, external validation of the Ottawa score has been inconsistent when applied in different cohorts of cancer patients [6,7]. In this study, we assessed whether the modified Ottawa score could accurately stratify the risk for VTE recurrence in an independent dataset. Since May 2000, we have asked to participate in a VTE cohort all consecutive patients aged 18 years or more seen at the outpatient clinic or admitted to Brest University Hospital for symptomatic deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE). For this analysis, we applied the modified Ottawa score in patients who were included in the cohort for a proximal symptomatic cancerassociated DVT of the lower limbs or symptomatic cancer-associated PE and no surgery in the preceding 3 months. Because we did not record exact cancer stage, we attributed a negative point for “absence of metastasis” instead of for “cancer stages I + II”. The primary end point of the study was recurrence of symptomatic VTE. The cumulative risk for VTE recurrence was estimated by using the Kaplan–Meier method. The study protocol was approved by our hospital scientific and ethics board. All patients gave informed consent. Between May 2000 and July 2010, 235 patients with cancerassociated VTE were included in the study. Of these, 79 patients were excluded due to recent cancer surgery (n = 45), isolated distal DVT (n = 29) or no follow-up (n = 14). Mean age of the 156 studied patients
was 69.5 ± 1.8 years, and 70 (44.9%) were female. There were 23 patients with lung cancer (14.7%), 17 with breast cancer (10.9%), 36 with past history of VTE (23.1%), and 94 without metastasis (60.2%). Fourteen patients had a recurrent VTE event during follow-up corresponding to an estimated 6-months cumulative recurrence rate of 11.9% (95% CI 7.2–19.4). When the modified Ottawa score was applied to our sample, 43 patients (27.6%) were classified at low risk for VTE recurrence, 62 (39.7%) at intermediate risk, and 51 (32.7%) at high risk (Table 1). The 6-month cumulative recurrence rate of VTE was 2.6% (95% CI 0.4–17.2) in low-risk patients (1 recurrence), 8.6% (95% CI 3.3–21.6) in intermediate-risk patients (4 recurrences), and 24.9% (95% CI 13.5– 43.1) in high-risk patients (9 recurrences) (p = 0.02 by log-rank test) (Fig. 1). In our dataset, the modified Ottawa score could categorize our patients into 3 groups at different risks for recurrent VTE. In particular, the model clearly identified low-risk and high-risk patients, with a 22% absolute difference in the risk for recurrent VTE between low-risk group and high-risk group. Two main points should be discussed. Firstly, the recurrence rate of VTE that we observed in the high-risk group (24.9%) was particularly high compared to the rate found in the original validation cohort (13.9%) [5]. Our patients were probably more severe than those included in the original validation cohort that was based on two randomized trials whose inclusion criteria enclosed extended life expectancy. Nevertheless, the overall recurrence rate observed in our patients is consistent with previous studies [3]. Secondly, by attributing a negative point to all patients without metastasis instead of cancer stage I + II as originally set in the derivation and validation studies, we may have missed patients who should have been classified into the intermediate risk group. However, when the predictor “cancer stage I + II” was also replaced by “absence of metastasis” in an independent Dutch cohort of 416 patients, the modified Ottawa score was still reproducible and offered an accurate estimation for the risk of recurrent VTE in cancer patients [7]. Cancer staging is not easy from a nononcologist assessment; therefore, giving a negative point to patients without metastasis would be the easiest way to accurately classify patients. In conclusion, our data bring out further evidence suggesting that the modified Ottawa score can identify patients at low or high risk for recurrence after a cancer-associated VTE event, using “no metastasis” as predictor instead of “cancer stage I + II”. If other external validation studies demonstrate that the absence of metastases clearly helps to stratify patients into a lower risk for recurrent VTE, the Ottawa score will certainly be implemented in order to tailor anticoagulation therapy in patients with cancer-associated VTE.
Conflict of interests To the best of our knowledge, no conflict of interest, financial or other, exists.
http://dx.doi.org/10.1016/j.ejim.2016.08.001 0953-6205/© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Astruc N, et al, External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.001
e2
Letter to the Editor
Table 1 Number of patients and number of VTE recurrences and deaths according to the sum of points obtained by applying the modified Ottawa score. Sum of points
Recurrence risk
Number of patients
Recurrent VTE N (%)
−1 0 1 2 3
Low Intermediate High
43 (27.6%) 62 (39.7%) 43 (27.6%) 5 (3.2%) 3 (1.9%)
1 (2.3%) 4 (6.45%) 6 (13.9%) 2 (40.0%) 1 (33.3%)
VTE: venous thromboembolism.
[2] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160(6):809–15. [3] Carrier M, Cameron C, Delluc A, Castellucci L, Khorana AA, Lee AY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res 2014;134(6):1214–9. [4] Louzada ML, Majeed H, Dao V, Wells PS. Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies. Blood Coagul Fibrinolysis 2011;22(2):86–91. [5] Louzada ML, Carrier M, Lazo-Langner A, Dao V, Kovacs MJ, Ramsay TO, et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation 2012;126(4):448–54. [6] Ahn S, Lim KS, Lee YS, Lee JL. Validation of the clinical prediction rule for recurrent venous thromboembolism in cancer patients: the Ottawa score. Support Care Cancer 2013;21(8):2309–13. [7] den Exter PL, Kooiman J, Huisman MV. Validation of the Ottawa prognostic score for the prediction of recurrent venous thromboembolism in patients with cancerassociated thrombosis. J Thromb Haemost 2013;11(5):998–1000.
Nolwenn Astruc Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest F-29609, France Jean-Christophe Ianotto Oncology & Haematology Institute, Brest University Hospital, Brest F-29609, France Brest University (Université de Bretagne Occidentale), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Equipe d'Accueil 3878, Brest F-29609, France Jean-Philippe Metges Oncology & Haematology Institute, Brest University Hospital, Brest F-29609, France Fig. 1. Cumulative risk of recurrent venous thromboembolism according to risk category.
Acknowledgment The study was supported by grants from INSERM (Contrat de Recherche Stratégique 2001, CRES No. 4CR05G), from Région Bretagne (Programme 1044-04013235 no. 1440) and Programme Hospitalier de Recherche Clinique 2000. The Centre Hospitalier Régional et Universitaire de Brest promoted the study. The funders of this study had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.
References [1] Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166(4):458–64.
Karine Lacut Brest University (Université de Bretagne Occidentale), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Equipe d'Accueil 3878, Brest F-29609, France Centre d'Investigation Clinique INSERM 1412, Brest University Hospital, Brest F-29609, France Aurélien Delluc Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest F-29609, France Brest University (Université de Bretagne Occidentale), Groupe d'Etude de la Thrombose de Bretagne Occidentale, Equipe d'Accueil 3878, Brest F-29609, France Corresponding author at: EA 3878, Département de Médecine interne et de pneumologie, Centre hospitalier universitaire de Brest, Hôpital de la Cavale Blanche, 29609, Brest Cedex, France. 29 July 2016 Available online xxxx
Please cite this article as: Astruc N, et al, External validation of the modified Ottawa score for risk stratification of recurrent cancer-associated thrombosis, Eur J Intern Med (2016), http://dx.doi.org/10.1016/j.ejim.2016.08.001