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A health systems approach to risk stratification
Thrombosis Research 136 (2015) 1049–1050
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
A health systems approach to risk stratification
In 2008, my colleagues and I published a risk stratification tool to identify ambulatory cancer patients at high risk for venous thromboembolism (VTE), an increasingly common, morbid and potentially lethal complication of malignancy [1]. This study, funded by the National Cancer Institute, characterized the association of VTE with multiple variables in a derivation cohort of 2701 cancer outpatients from a prospective observational registry. A risk model was derived and validated in an independent cohort of 1365 patients from the same registry — a split sample approach to model validation. In this initial study, rates of VTE in the derivation and validation cohorts, respectively, were 0.8% and 0.3% in low-risk (score = 0), 1.8% and 2% in intermediate-risk (score = 1–2), and 7.1% and 6.7% in high-risk (score ≥ 3) patients over a median of 2.5 months. Although my co-authors and I were enthused about these findings, we were cautious in interpreting the results, emphasizing that it was “important to further validate this model”. The past several years have seen multiple research teams attempt to validate this risk model in prospective and retrospective cohort studies. It has been gratifying to see that these studies have been largely successful, confirming external validation of the original risk model in diverse geographic and healthcare settings (reviewed in [2]). All told, over 12,000 patients have been formally evaluated using the risk score. Based on this very extensive experience, the latest American Society of Clinical Oncology guidelines recommend the risk score as the only validated risk assessment tool for predicting cancer-associated thrombosis [3]. Modifications of the original risk score with the addition of biomarkers have been proposed but await validation themselves [4]. (As an aside, it is important to clarify that some studies have attempted to use the risk score in a single site of disease, such as germ cell tumors or lymphoma, to predict VTE. Such a use of the score should be understood to represent a modification of the original score since primary site of cancer is a crucial variable in the scoring system). In 2015, then, how can this validated risk score be best utilized? Three approaches can be considered (Fig. 1). First and most obvious is using the score to identify high-risk patients for thromboprophylaxis to prevent VTE in the ambulatory setting. Evidence to support this approach comes from the subgroup analyses of the two large clinical trials of thromboprophylaxis in ambulatory cancer patients. Verso et al. reported a post-hoc subgroup analysis of the PROTECHT study population and found approximately 12% of the population was highrisk (score ≥ 3) [5]. In this subgroup, rates of VTE were 11.1% in the placebo arm and 4.5% in the nadroparin arm and thus the number needed to treat (NNT) to prevent one event was 15, whereas the NNT was 50 for the overall study population. Similarly, George et al. reported in a per-protocol subgroup analysis of SAVE-ONCO that rates of VTE were reduced from 5.4% for placebo to 1.4% for semuloparin, for score ≥ 3 (HR 0.27) compared to 1.3% vs. 1% respectively for score = 0
http://dx.doi.org/10.1016/j.thromres.2015.10.008 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
[6]. There were no significant differences in bleeding rates. Ongoing randomized trials are using the risk score to identify high-risk patients as formal study eligibility criteria and results of these studies are eagerly anticipated. A second use of the risk score could be to screen high-risk patients for existing but subclinical VTE. A recent single institution study reported in this journal identified a 9% risk of VTE in high-risk patients (score ≥ 3) at baseline i.e., prior to initiating a new systemic therapy regimen [7]. Additional multi-center data are expected to be reported later this year and if these initial findings are confirmed, screening could potentially be advocated for. Finally, lack of patient education and awareness is an important issue in this setting. Most cancer patients are unaware that they are at high risk for VTE and of the warning signs and symptoms of pulmonary embolism and deep vein thrombosis [8,9]. Electronic medical records set to automatically alert a health care provider to the risk status of an individual patient could help ensure that education about VTE is given the appropriate priority. It is in this context that the report by Lustig et al. is of great interest [10]. The authors created a novel computerized process at Ottawa Regional Cancer Center to identify new cancer patients at higher risk for VTE, using the risk score discussed above. Of interest, the authors expanded the criteria for patient to be considered at higher risk to a score of 2 or higher, as opposed to 3 or higher in the original paper. Identification of such higher risk patients led to an electronic notification of the clinic nurse prior to the patient's appointment and subsequently to provision of educational material to the patient by the nurse. In addition to education, patients were also followed for VTE outcomes for up to 3 months following initial contact as part of a prospective cohort study. Overall, 25% of 580 eligible patients were found to have a score of 2 or higher; of these, 11% developed symptomatic VTE. These results have several important implications. First, and most important, Lustig et al. [10] provide proof-of-concept that the risk score can be incorporated electronically into a clinical workflow that leads to an action by a health care provider. In this particular setting, the alert led to a nurse providing education to a higher risk patient; in future settings, one can imagine the same alert being used as a trigger to screen such patients for VTE or to prescribe thromboprophylaxis. Second, the investigators make a convincing argument that the cut-off for higher risk should be a score of 2 or higher, a point previously raised in a prospective cohort study by the Vienna CATS group who showed that such patients were at similar substantially elevated risk for VTE [4]. Third, the report provides a sense of the real world subgroup of cancer patients that are at potentially higher-risk: approximately 25% of all newly diagnosed cancer patients who have not already had a VTE or are already on anticoagulation. Fourth, the study again validates that the risk score, in a real-world setting, is in fact effective at identifying
1050
Editorial
teams interested in improving outcomes in large health systems should take note. Conflicts of Interest Dr. Khorana has received research funding and consulting honoraria from Janssen, Genentech, Sanofi and Leo Pharma. Acknowledgments Dr. Khorana acknowledges the research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research, and the Scott Hamilton CARES Initiative. References
Fig. 1. Utilizing a validated risk score for cancer-associated venous thromboembolism in the clinical setting. VTE, venous thromboembolism.
patients at risk for VTE. The authors are to be congratulated on studying this intervention in a prospective, IRB-approved cohort study which adds to the validity of their findings. Ironically, the relative ease of implementation of the risk score as it currently stands argues against further modification of the score with the addition of other biomarkers. In our original paper, my co-authors and I had suggested that additional variables could improve the robustness of the score given the C statistic of 0.7. A future novel biomarker added to the score would require ordering a special test as opposed to the automatic workflow described in this report since the risk score incorporates variables such as type of cancer, body mass index and a complete blood count — all of which are generally available for cancer patients at time of first visit. Thus, a biomarker would have to either substantially improve the performance of the score or completely replace it to overcome this ease-of-use or “good enough” argument for the score in its current avatar. The past decade has seen important progress in our understanding of cancer-associated thrombosis. The work done by several research groups in this field to study and validate the risk score and clarify expected VTE rates is a terrific example of collaborative science. Now, however, it is equally important to implement the findings in ways that are meaningful for our patients and that can reduce the burden and consequences of cancer-associated VTE. This important report by Lustig et al. [10] shows us how this next step can be achieved. Quality
[1] A.A. Khorana, N.M. Kuderer, E. Culakova, G.H. Lyman, C.W. Francis, Development and validation of a predictive model for chemotherapy-associated thrombosis, Blood 111 (10) (May 15, 2008) 4902–4907. [2] A.A. Khorana, K.R. McCrae, Risk stratification strategies for cancer-associated thrombosis: an update, Thromb. Res. 133 (Suppl 2) (May 2014) S35–S38. [3] G.H. Lyman, A.A. Khorana, N.M. Kuderer, et al., Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 31 (17) (Jun. 10, 2013) 2189–2204. [4] C. Ay, D. Dunkler, C. Marosi, et al., Prediction of venous thromboembolism in cancer patients. Blood 116 (24) (Dec. 9, 2010) 5377–5382. [5] M. Verso, G. Agnelli, S. Barni, G. Gasparini, R. Labianca, A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score, Intern. Emerg. Med. (May 1, 2012). [6] D.J. George, G. Agnelli, W. Fisher, et al., Blood (206) (. 2011). [7] A.A. Khorana, D. Rubens, C.W. Francis, Screening high-risk cancer patients for VTE: a prospective observational study, Thromb. Res. 134 (6) (Dec. 2014) 1205–1207. [8] T. Sousou, A.A. Khorana, Cancer patients and awareness of venous thromboembolism, Cancer Investig. 28 (1) (Jan. 2010) 44–45. [9] A. Aggarwal, L. Fullam, A.P. Brownstein, et al., Deep vein thrombosis (DVT) and pulmonary embolism (PE): awareness and prophylaxis practices reported by patients with cancer, Cancer Investig. (Aug. 19, 2015) 1–6. [10] D.B. Lustig, R. Rodriguez, P.S. Wells, Implementation and validation of a risk stratification method at the Ottawa Hospital to guide thromboprophylaxis in ambulatory cancer patients at intermediate-high risk for venous thrombosis, Thromb. Res. 136 (6) (Aug. 4, 2015) 1099–1102.
Alok A. Khorana Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA Corresponding author at: 9500 Euclid Ave, R35, Cleveland, OH 44195, USA. E-mail address: [email protected] 9 September 2015
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
A health systems approach to risk stratification
In 2008, my colleagues and I published a risk stratification tool to identify ambulatory cancer patients at high risk for venous thromboembolism (VTE), an increasingly common, morbid and potentially lethal complication of malignancy [1]. This study, funded by the National Cancer Institute, characterized the association of VTE with multiple variables in a derivation cohort of 2701 cancer outpatients from a prospective observational registry. A risk model was derived and validated in an independent cohort of 1365 patients from the same registry — a split sample approach to model validation. In this initial study, rates of VTE in the derivation and validation cohorts, respectively, were 0.8% and 0.3% in low-risk (score = 0), 1.8% and 2% in intermediate-risk (score = 1–2), and 7.1% and 6.7% in high-risk (score ≥ 3) patients over a median of 2.5 months. Although my co-authors and I were enthused about these findings, we were cautious in interpreting the results, emphasizing that it was “important to further validate this model”. The past several years have seen multiple research teams attempt to validate this risk model in prospective and retrospective cohort studies. It has been gratifying to see that these studies have been largely successful, confirming external validation of the original risk model in diverse geographic and healthcare settings (reviewed in [2]). All told, over 12,000 patients have been formally evaluated using the risk score. Based on this very extensive experience, the latest American Society of Clinical Oncology guidelines recommend the risk score as the only validated risk assessment tool for predicting cancer-associated thrombosis [3]. Modifications of the original risk score with the addition of biomarkers have been proposed but await validation themselves [4]. (As an aside, it is important to clarify that some studies have attempted to use the risk score in a single site of disease, such as germ cell tumors or lymphoma, to predict VTE. Such a use of the score should be understood to represent a modification of the original score since primary site of cancer is a crucial variable in the scoring system). In 2015, then, how can this validated risk score be best utilized? Three approaches can be considered (Fig. 1). First and most obvious is using the score to identify high-risk patients for thromboprophylaxis to prevent VTE in the ambulatory setting. Evidence to support this approach comes from the subgroup analyses of the two large clinical trials of thromboprophylaxis in ambulatory cancer patients. Verso et al. reported a post-hoc subgroup analysis of the PROTECHT study population and found approximately 12% of the population was highrisk (score ≥ 3) [5]. In this subgroup, rates of VTE were 11.1% in the placebo arm and 4.5% in the nadroparin arm and thus the number needed to treat (NNT) to prevent one event was 15, whereas the NNT was 50 for the overall study population. Similarly, George et al. reported in a per-protocol subgroup analysis of SAVE-ONCO that rates of VTE were reduced from 5.4% for placebo to 1.4% for semuloparin, for score ≥ 3 (HR 0.27) compared to 1.3% vs. 1% respectively for score = 0
http://dx.doi.org/10.1016/j.thromres.2015.10.008 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
[6]. There were no significant differences in bleeding rates. Ongoing randomized trials are using the risk score to identify high-risk patients as formal study eligibility criteria and results of these studies are eagerly anticipated. A second use of the risk score could be to screen high-risk patients for existing but subclinical VTE. A recent single institution study reported in this journal identified a 9% risk of VTE in high-risk patients (score ≥ 3) at baseline i.e., prior to initiating a new systemic therapy regimen [7]. Additional multi-center data are expected to be reported later this year and if these initial findings are confirmed, screening could potentially be advocated for. Finally, lack of patient education and awareness is an important issue in this setting. Most cancer patients are unaware that they are at high risk for VTE and of the warning signs and symptoms of pulmonary embolism and deep vein thrombosis [8,9]. Electronic medical records set to automatically alert a health care provider to the risk status of an individual patient could help ensure that education about VTE is given the appropriate priority. It is in this context that the report by Lustig et al. is of great interest [10]. The authors created a novel computerized process at Ottawa Regional Cancer Center to identify new cancer patients at higher risk for VTE, using the risk score discussed above. Of interest, the authors expanded the criteria for patient to be considered at higher risk to a score of 2 or higher, as opposed to 3 or higher in the original paper. Identification of such higher risk patients led to an electronic notification of the clinic nurse prior to the patient's appointment and subsequently to provision of educational material to the patient by the nurse. In addition to education, patients were also followed for VTE outcomes for up to 3 months following initial contact as part of a prospective cohort study. Overall, 25% of 580 eligible patients were found to have a score of 2 or higher; of these, 11% developed symptomatic VTE. These results have several important implications. First, and most important, Lustig et al. [10] provide proof-of-concept that the risk score can be incorporated electronically into a clinical workflow that leads to an action by a health care provider. In this particular setting, the alert led to a nurse providing education to a higher risk patient; in future settings, one can imagine the same alert being used as a trigger to screen such patients for VTE or to prescribe thromboprophylaxis. Second, the investigators make a convincing argument that the cut-off for higher risk should be a score of 2 or higher, a point previously raised in a prospective cohort study by the Vienna CATS group who showed that such patients were at similar substantially elevated risk for VTE [4]. Third, the report provides a sense of the real world subgroup of cancer patients that are at potentially higher-risk: approximately 25% of all newly diagnosed cancer patients who have not already had a VTE or are already on anticoagulation. Fourth, the study again validates that the risk score, in a real-world setting, is in fact effective at identifying
1050
Editorial
teams interested in improving outcomes in large health systems should take note. Conflicts of Interest Dr. Khorana has received research funding and consulting honoraria from Janssen, Genentech, Sanofi and Leo Pharma. Acknowledgments Dr. Khorana acknowledges the research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research, and the Scott Hamilton CARES Initiative. References
Fig. 1. Utilizing a validated risk score for cancer-associated venous thromboembolism in the clinical setting. VTE, venous thromboembolism.
patients at risk for VTE. The authors are to be congratulated on studying this intervention in a prospective, IRB-approved cohort study which adds to the validity of their findings. Ironically, the relative ease of implementation of the risk score as it currently stands argues against further modification of the score with the addition of other biomarkers. In our original paper, my co-authors and I had suggested that additional variables could improve the robustness of the score given the C statistic of 0.7. A future novel biomarker added to the score would require ordering a special test as opposed to the automatic workflow described in this report since the risk score incorporates variables such as type of cancer, body mass index and a complete blood count — all of which are generally available for cancer patients at time of first visit. Thus, a biomarker would have to either substantially improve the performance of the score or completely replace it to overcome this ease-of-use or “good enough” argument for the score in its current avatar. The past decade has seen important progress in our understanding of cancer-associated thrombosis. The work done by several research groups in this field to study and validate the risk score and clarify expected VTE rates is a terrific example of collaborative science. Now, however, it is equally important to implement the findings in ways that are meaningful for our patients and that can reduce the burden and consequences of cancer-associated VTE. This important report by Lustig et al. [10] shows us how this next step can be achieved. Quality
[1] A.A. Khorana, N.M. Kuderer, E. Culakova, G.H. Lyman, C.W. Francis, Development and validation of a predictive model for chemotherapy-associated thrombosis, Blood 111 (10) (May 15, 2008) 4902–4907. [2] A.A. Khorana, K.R. McCrae, Risk stratification strategies for cancer-associated thrombosis: an update, Thromb. Res. 133 (Suppl 2) (May 2014) S35–S38. [3] G.H. Lyman, A.A. Khorana, N.M. Kuderer, et al., Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 31 (17) (Jun. 10, 2013) 2189–2204. [4] C. Ay, D. Dunkler, C. Marosi, et al., Prediction of venous thromboembolism in cancer patients. Blood 116 (24) (Dec. 9, 2010) 5377–5382. [5] M. Verso, G. Agnelli, S. Barni, G. Gasparini, R. Labianca, A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score, Intern. Emerg. Med. (May 1, 2012). [6] D.J. George, G. Agnelli, W. Fisher, et al., Blood (206) (. 2011). [7] A.A. Khorana, D. Rubens, C.W. Francis, Screening high-risk cancer patients for VTE: a prospective observational study, Thromb. Res. 134 (6) (Dec. 2014) 1205–1207. [8] T. Sousou, A.A. Khorana, Cancer patients and awareness of venous thromboembolism, Cancer Investig. 28 (1) (Jan. 2010) 44–45. [9] A. Aggarwal, L. Fullam, A.P. Brownstein, et al., Deep vein thrombosis (DVT) and pulmonary embolism (PE): awareness and prophylaxis practices reported by patients with cancer, Cancer Investig. (Aug. 19, 2015) 1–6. [10] D.B. Lustig, R. Rodriguez, P.S. Wells, Implementation and validation of a risk stratification method at the Ottawa Hospital to guide thromboprophylaxis in ambulatory cancer patients at intermediate-high risk for venous thrombosis, Thromb. Res. 136 (6) (Aug. 4, 2015) 1099–1102.
Alok A. Khorana Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA Corresponding author at: 9500 Euclid Ave, R35, Cleveland, OH 44195, USA. E-mail address: [email protected] 9 September 2015