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Comparison of the Pulmonary Embolism Severity Index to a Simplified Version: Classification and Clinical Outcomes
Thrombosis Research 133 (2014) 515–516
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Comparison of the Pulmonary Embolism Severity Index to a Simplified Version: Classification and Clinical Outcomes
Dear Editors, The original Pulmonary Embolism Severity Index (PESI) is a validated clinical tool to predict outcomes in patients with acute pulmonary embolism [1–6]. Based on 11 readily available clinical variables the PESI permits calculation of a point score that stratifies patients into five classes (I-V) of increasing risk of short-term mortality (Table 1). Patients in risk classes I and II (≤85 points) are at low risk, with a predicted probability of death within 30 days b 2.5% [5]. The international, open-label, randomized non-inferiority Outpatient Treatment of Pulmonary Embolism (OTPE) trial demonstrated that selected low risk patients identified using the PESI can be safely treated initially in the outpatient setting [7]. Jiménez et al. developed a simplified version of the PESI (called “sPESI”) consisting of only six variables [8]. In contrast to the original PESI, the sPESI includes age as a dichotomized variable (N80 years), combines heart failure and chronic lung disease as a single variable (cardiopulmonary disease), and omits the variables male gender, respiratory rate, and altered mental status (Table 1). Each of the sPESI variables has a weight of 1 point, and patients with none of the sPESI variables (0 points) are classified at low risk for short-term mortality.
Table 1 Pulmonary Embolism Severity Index (PESI) and the simplified PESI. Score Variable
Original PESIa
Simplified PESIb
Age N80 y Male sex History of cancer History of heart failure History of chronic lung disease Pulse ≥110 beats/min Systolic blood pressure b100 mmHg Respiratory rate ≥30 breaths/min Temperature b36 °C Altered mental status Arterial SO2 level b90%
Age in years +10 +30 +10 +10
1
1c
+20 +30
1 1
1
+20 +20 +60 +20
1
a) A total point score for a given patient is obtained by summing the patient’s age in years and the points for each predictor when present. The score corresponds with the following risk classes: 65 or less, class I; 66 to 85, class II; 86 to 105, class III; 106 to 125, class IV; and more than 125, class V. Patients in risk classes I and II are defined as being at low risk. b) A total point score for a given patient is obtained by summing the points. The score corresponds with the following risk classes: 0, low risk; 1 or more, high risk. Empty cells indicate that the variable was not included. c) The variables were combined into a single category of chronic cardiopulmonary disease. 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.12.012
A potential advantage of the sPESI is its greater simplicity for clinical use. Retrospective comparisons indicate that the sPESI identifies low risk patients with accuracy and discriminative power similar to the original PESI [9–11]. However, these comparisons did not directly address classification. We sought to compare the PESI and sPESI, notably with respect to classification, in the cohort of patients with pulmonary embolism who were screened for participation in the OPTE trial [7]. We analyzed data from the OTPE trial conducted at 19 emergency departments in Switzerland, France, Belgium, and the United States between February 2007 and June 2010 (ClinicalTrials.gov, number NCT00425542) [7]. The trial screened 1557 consecutive adults aged ≥ 18 years with acute, objectively confirmed pulmonary embolism and randomized 344 consenting, low-risk patients based on the PESI (risk classes II and II) to outpatient or inpatient care with subcutaneous enoxaparin (≥5 days) and vitamin K antagonists (≥90 days) [7]. In this trial, the PESI variables were collected prospectively and rigorously for all patients screened. The trial was approved by the ethics committee at each study site. We assessed the agreement between the PESI and sPESI in the classification of patients with pulmonary embolism using the unweighted kappa statistic and characterized reasons for differential classification in an unselected cohort of 1557 patients with pulmonary embolism screened for the OTPE trial. We also examined outcomes by sPESI classification in 339 PESI-defined low risk patients enrolled in the OTPE trial who had a complete 90-day follow-up. Among 1557 screened patients with pulmonary embolism, the PESI classified more screened patients as low risk (n = 778; 50.0%) than did the sPESI (n = 661; 42.5%, McNemar’s p b 0.001; Table 2). Agreement between the sPESI and the PESI was substantial, with an unweighted kappa statistic of 0.72 (95% confidence interval: 0.67 to 0.77). The sPESI classified 168 low risk patients as higher risk and 51 higher risk patients as low risk (Table 2). The major reasons that 168 PESI low risk patients were classified as higher risk by the sPESI were pulse ≥ 110/min. (n = 77), male sex (n = 48), history of chronic lung disease (n = 29), age N 80 years (n = 25), arterial SO2 b90%, and/or history of cancer (n = 18). The 51 PESI higher risk patients who were classified as low risk based on the sPESI were either male (n = 41) or had respiratory rate ≥30/min (n = 6), temperature b 36 °C (n = 11) or altered mental status (n = 9). When we reclassified the 339 PESI low risk patients enrolled in the OTPE trial based on the sPESI, 293 (86.4%) were classified as low risk (88.3% of the 171 OTPE outpatients and 84.5% of the 168 OTPE inpatients). The sPESI classified 46 OTPE participants as higher risk because they were aged N 80 years (n = 4) or had history of cancer (n = 4), cardiopulmonary disease (n = 17), or pulse rate ≥ 110/min. (n = 21). In the OTPE trial, three outpatients had major bleeding, one outpatient had nonfatal recurrent pulmonary embolism and two participants died (one outpatient, one inpatient) [7]. While the major bleedings and deaths were classified as low risk by both the PESI and the sPESI, the outpatient who had recurrent pulmonary embolism was classified as
516
Letter to the Editors-in-Chief
high risk by the sPESI, as were 45 other patients with an uneventful follow-up. In the cohort screened for the OTPE trial, the substantial agreement between the PESI and sPESI is not surprising given that the sPESI is derived directly from the PESI. Consistent with other reports [9,10] the PESI identified more patients as low risk in the OTPE screened cohort. In our OTPE screening population, both clinical prognostic models identified low risk cohorts. Our results are consistent with a retrospective analysis in which low-risk patients based on the PESI and sPESI were safely treated as outpatients [4]. The interrater agreement in our study was improved compared to a retrospective analysis of 357 patients with pulmonary embolism, where the interrater agreement between the PESI and sPESI was only fair, with a kappa statistic of 0.62 [10]. The differential classification for the sPESI and PESI can be explained by differences in the derivation samples. Patients in the derivation sample of the sPESI were older, more likely to be male and to have cancer and arterial oxygen desaturation than patients in the derivation sample of the PESI. A limitation to our study is that no outcome data are available for 51 screened patients who did not participate in the OTPE trial who were low risk on the sPESI but higher risk on the PESI. One patient who experienced a nonfatal pulmonary embolism would have been excluded from the OTPE study if the sPESI had been the basis for screening. Because of intrinsic limitations of our data, a formal comparison of safety between the two scores was not feasible. In conclusion, the PESI and sPESI demonstrated substantial agreement in classifying a cohort of patients with pulmonary embolism. The PESI identified more patients as low risk in the OTPE screened cohort. This differential misclassification indicates that safety of the outpatient care of low-risk patients based on the sPESI must be evaluated in a prospective outcome study before this simplified prognostic model is adopted widely. Conflict of Interest Statement The authors have no conflict of interest. Author contributions RAS, MR, DMY, and DA conceived and designed the study. DMY and DA obtained research funding. DMY and DA supervised the conduct of the trial and data collection. RAS and NP performed data analyses. AKS drafted the article, and all authors contributed substantially to its revision. DA takes responsibility for the paper as a whole. Funding and support This work was supported by grants from the Swiss National Science Foundation (3200B0-1121; 33CSCO-122659) and the U.S. National Heart, Lung, and Blood Institute (1R01HL085565-01A2).
Table 2 Risk classification of 1557 patients with pulmonary embolism screened for the OPTE trial according to the PESI and the sPESI. sPESI Classification
PESI Classification Low risk Higher risk
Low risk Higher risk Total
610 168 778
Total 51 728 779
661 896 1557
Abbreviations: OTPE, Outpatient Treatment of Pulmonary Embolism; PESI, Pulmonary Embolism Severity Index; sPESI, simplified Pulmonary Embolism Severity Index.
[4] Erkens PM, Gandara E, Wells PS, Shen AY, Bose G, Le Gal G, et al. Does the Pulmonary Embolism Severity Index accurately identify low risk patients eligible for outpatient treatment? Thromb Res 2012;129:710–4. [5] Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041–6. [6] Fraga M, Taffe P, Mean M, Hugli O, Witzig S, Waeber G, et al. The inter-rater reliability of the Pulmonary Embolism Severity Index. Thromb Haemost 2010; 104:1258–62. [7] Aujesky D, Roy PM, Verschuren F, Righini M, Osterwalder J, Egloff M, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011;378:41–8. [8] Jimenez D, Aujesky D, Moores L, Gomez V, Lobo JL, Uresandi F, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383–9. [9] Venetz C, Jimenez D, Mean M, Aujesky D. A comparison of the original and simplified Pulmonary Embolism Severity Index. Thromb Haemost 2011;106:423–8. [10] Righini M, Roy PM, Meyer G, Verschuren F, Aujesky D, Le Gal G. The Simplified Pulmonary Embolism Severity Index (PESI): validation of a clinical prognostic model for pulmonary embolism. J Thromb Haemost 2011;9:2115–7. [11] Zhou XY, Ben SQ, Chen HL, Ni SS. The prognostic value of pulmonary embolism severity index in acute pulmonary embolism: a meta-analysis. Respir Res 2012;13:111.
Anna K. Stuck Division of General Internal Medicine, Bern University Hospital, Bern, Switzerland Corresponding author at: Division of General Internal Medicine Bern University Hospital, Inselspital 3010 Bern, Switzerland. Tel.: +41 31 632 2111; fax: +41 31 632 0638. E-mail address: [email protected]. Roslyn A. Stone Nathan Pugh Department of Biostatistics, University of Pittsburgh Pittsburgh, PA, USA
Marc Righini Division of Angiology and Hemostasis, University of Geneva, Geneva, Switzerland
Donald M. Yealy Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, USA
References [1] Chan CM, Woods C, Shorr AF. The validation and reproducibility of the pulmonary embolism severity index. J Thromb Haemost 2010;8:1509–14. [2] Aujesky D, Perrier A, Roy PM, Stone RA, Cornuz J, Meyer G, et al. Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism. J Intern Med 2007;261:597–604. [3] Donze J, Le Gal G, Fine MJ, Roy PM, Sanchez O, Verschuren F, et al. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost 2008;100:943–8.
Drahomir Aujesky Division of General Internal Medicine, Bern University Hospital, Bern, Switzerland 20 November 2013
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Letter to the Editors-in-Chief Comparison of the Pulmonary Embolism Severity Index to a Simplified Version: Classification and Clinical Outcomes
Dear Editors, The original Pulmonary Embolism Severity Index (PESI) is a validated clinical tool to predict outcomes in patients with acute pulmonary embolism [1–6]. Based on 11 readily available clinical variables the PESI permits calculation of a point score that stratifies patients into five classes (I-V) of increasing risk of short-term mortality (Table 1). Patients in risk classes I and II (≤85 points) are at low risk, with a predicted probability of death within 30 days b 2.5% [5]. The international, open-label, randomized non-inferiority Outpatient Treatment of Pulmonary Embolism (OTPE) trial demonstrated that selected low risk patients identified using the PESI can be safely treated initially in the outpatient setting [7]. Jiménez et al. developed a simplified version of the PESI (called “sPESI”) consisting of only six variables [8]. In contrast to the original PESI, the sPESI includes age as a dichotomized variable (N80 years), combines heart failure and chronic lung disease as a single variable (cardiopulmonary disease), and omits the variables male gender, respiratory rate, and altered mental status (Table 1). Each of the sPESI variables has a weight of 1 point, and patients with none of the sPESI variables (0 points) are classified at low risk for short-term mortality.
Table 1 Pulmonary Embolism Severity Index (PESI) and the simplified PESI. Score Variable
Original PESIa
Simplified PESIb
Age N80 y Male sex History of cancer History of heart failure History of chronic lung disease Pulse ≥110 beats/min Systolic blood pressure b100 mmHg Respiratory rate ≥30 breaths/min Temperature b36 °C Altered mental status Arterial SO2 level b90%
Age in years +10 +30 +10 +10
1
1c
+20 +30
1 1
1
+20 +20 +60 +20
1
a) A total point score for a given patient is obtained by summing the patient’s age in years and the points for each predictor when present. The score corresponds with the following risk classes: 65 or less, class I; 66 to 85, class II; 86 to 105, class III; 106 to 125, class IV; and more than 125, class V. Patients in risk classes I and II are defined as being at low risk. b) A total point score for a given patient is obtained by summing the points. The score corresponds with the following risk classes: 0, low risk; 1 or more, high risk. Empty cells indicate that the variable was not included. c) The variables were combined into a single category of chronic cardiopulmonary disease. 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.12.012
A potential advantage of the sPESI is its greater simplicity for clinical use. Retrospective comparisons indicate that the sPESI identifies low risk patients with accuracy and discriminative power similar to the original PESI [9–11]. However, these comparisons did not directly address classification. We sought to compare the PESI and sPESI, notably with respect to classification, in the cohort of patients with pulmonary embolism who were screened for participation in the OPTE trial [7]. We analyzed data from the OTPE trial conducted at 19 emergency departments in Switzerland, France, Belgium, and the United States between February 2007 and June 2010 (ClinicalTrials.gov, number NCT00425542) [7]. The trial screened 1557 consecutive adults aged ≥ 18 years with acute, objectively confirmed pulmonary embolism and randomized 344 consenting, low-risk patients based on the PESI (risk classes II and II) to outpatient or inpatient care with subcutaneous enoxaparin (≥5 days) and vitamin K antagonists (≥90 days) [7]. In this trial, the PESI variables were collected prospectively and rigorously for all patients screened. The trial was approved by the ethics committee at each study site. We assessed the agreement between the PESI and sPESI in the classification of patients with pulmonary embolism using the unweighted kappa statistic and characterized reasons for differential classification in an unselected cohort of 1557 patients with pulmonary embolism screened for the OTPE trial. We also examined outcomes by sPESI classification in 339 PESI-defined low risk patients enrolled in the OTPE trial who had a complete 90-day follow-up. Among 1557 screened patients with pulmonary embolism, the PESI classified more screened patients as low risk (n = 778; 50.0%) than did the sPESI (n = 661; 42.5%, McNemar’s p b 0.001; Table 2). Agreement between the sPESI and the PESI was substantial, with an unweighted kappa statistic of 0.72 (95% confidence interval: 0.67 to 0.77). The sPESI classified 168 low risk patients as higher risk and 51 higher risk patients as low risk (Table 2). The major reasons that 168 PESI low risk patients were classified as higher risk by the sPESI were pulse ≥ 110/min. (n = 77), male sex (n = 48), history of chronic lung disease (n = 29), age N 80 years (n = 25), arterial SO2 b90%, and/or history of cancer (n = 18). The 51 PESI higher risk patients who were classified as low risk based on the sPESI were either male (n = 41) or had respiratory rate ≥30/min (n = 6), temperature b 36 °C (n = 11) or altered mental status (n = 9). When we reclassified the 339 PESI low risk patients enrolled in the OTPE trial based on the sPESI, 293 (86.4%) were classified as low risk (88.3% of the 171 OTPE outpatients and 84.5% of the 168 OTPE inpatients). The sPESI classified 46 OTPE participants as higher risk because they were aged N 80 years (n = 4) or had history of cancer (n = 4), cardiopulmonary disease (n = 17), or pulse rate ≥ 110/min. (n = 21). In the OTPE trial, three outpatients had major bleeding, one outpatient had nonfatal recurrent pulmonary embolism and two participants died (one outpatient, one inpatient) [7]. While the major bleedings and deaths were classified as low risk by both the PESI and the sPESI, the outpatient who had recurrent pulmonary embolism was classified as
516
Letter to the Editors-in-Chief
high risk by the sPESI, as were 45 other patients with an uneventful follow-up. In the cohort screened for the OTPE trial, the substantial agreement between the PESI and sPESI is not surprising given that the sPESI is derived directly from the PESI. Consistent with other reports [9,10] the PESI identified more patients as low risk in the OTPE screened cohort. In our OTPE screening population, both clinical prognostic models identified low risk cohorts. Our results are consistent with a retrospective analysis in which low-risk patients based on the PESI and sPESI were safely treated as outpatients [4]. The interrater agreement in our study was improved compared to a retrospective analysis of 357 patients with pulmonary embolism, where the interrater agreement between the PESI and sPESI was only fair, with a kappa statistic of 0.62 [10]. The differential classification for the sPESI and PESI can be explained by differences in the derivation samples. Patients in the derivation sample of the sPESI were older, more likely to be male and to have cancer and arterial oxygen desaturation than patients in the derivation sample of the PESI. A limitation to our study is that no outcome data are available for 51 screened patients who did not participate in the OTPE trial who were low risk on the sPESI but higher risk on the PESI. One patient who experienced a nonfatal pulmonary embolism would have been excluded from the OTPE study if the sPESI had been the basis for screening. Because of intrinsic limitations of our data, a formal comparison of safety between the two scores was not feasible. In conclusion, the PESI and sPESI demonstrated substantial agreement in classifying a cohort of patients with pulmonary embolism. The PESI identified more patients as low risk in the OTPE screened cohort. This differential misclassification indicates that safety of the outpatient care of low-risk patients based on the sPESI must be evaluated in a prospective outcome study before this simplified prognostic model is adopted widely. Conflict of Interest Statement The authors have no conflict of interest. Author contributions RAS, MR, DMY, and DA conceived and designed the study. DMY and DA obtained research funding. DMY and DA supervised the conduct of the trial and data collection. RAS and NP performed data analyses. AKS drafted the article, and all authors contributed substantially to its revision. DA takes responsibility for the paper as a whole. Funding and support This work was supported by grants from the Swiss National Science Foundation (3200B0-1121; 33CSCO-122659) and the U.S. National Heart, Lung, and Blood Institute (1R01HL085565-01A2).
Table 2 Risk classification of 1557 patients with pulmonary embolism screened for the OPTE trial according to the PESI and the sPESI. sPESI Classification
PESI Classification Low risk Higher risk
Low risk Higher risk Total
610 168 778
Total 51 728 779
661 896 1557
Abbreviations: OTPE, Outpatient Treatment of Pulmonary Embolism; PESI, Pulmonary Embolism Severity Index; sPESI, simplified Pulmonary Embolism Severity Index.
[4] Erkens PM, Gandara E, Wells PS, Shen AY, Bose G, Le Gal G, et al. Does the Pulmonary Embolism Severity Index accurately identify low risk patients eligible for outpatient treatment? Thromb Res 2012;129:710–4. [5] Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041–6. [6] Fraga M, Taffe P, Mean M, Hugli O, Witzig S, Waeber G, et al. The inter-rater reliability of the Pulmonary Embolism Severity Index. Thromb Haemost 2010; 104:1258–62. [7] Aujesky D, Roy PM, Verschuren F, Righini M, Osterwalder J, Egloff M, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011;378:41–8. [8] Jimenez D, Aujesky D, Moores L, Gomez V, Lobo JL, Uresandi F, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010;170:1383–9. [9] Venetz C, Jimenez D, Mean M, Aujesky D. A comparison of the original and simplified Pulmonary Embolism Severity Index. Thromb Haemost 2011;106:423–8. [10] Righini M, Roy PM, Meyer G, Verschuren F, Aujesky D, Le Gal G. The Simplified Pulmonary Embolism Severity Index (PESI): validation of a clinical prognostic model for pulmonary embolism. J Thromb Haemost 2011;9:2115–7. [11] Zhou XY, Ben SQ, Chen HL, Ni SS. The prognostic value of pulmonary embolism severity index in acute pulmonary embolism: a meta-analysis. Respir Res 2012;13:111.
Anna K. Stuck Division of General Internal Medicine, Bern University Hospital, Bern, Switzerland Corresponding author at: Division of General Internal Medicine Bern University Hospital, Inselspital 3010 Bern, Switzerland. Tel.: +41 31 632 2111; fax: +41 31 632 0638. E-mail address: [email protected]. Roslyn A. Stone Nathan Pugh Department of Biostatistics, University of Pittsburgh Pittsburgh, PA, USA
Marc Righini Division of Angiology and Hemostasis, University of Geneva, Geneva, Switzerland
Donald M. Yealy Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA, USA
References [1] Chan CM, Woods C, Shorr AF. The validation and reproducibility of the pulmonary embolism severity index. J Thromb Haemost 2010;8:1509–14. [2] Aujesky D, Perrier A, Roy PM, Stone RA, Cornuz J, Meyer G, et al. Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism. J Intern Med 2007;261:597–604. [3] Donze J, Le Gal G, Fine MJ, Roy PM, Sanchez O, Verschuren F, et al. Prospective validation of the Pulmonary Embolism Severity Index. A clinical prognostic model for pulmonary embolism. Thromb Haemost 2008;100:943–8.
Drahomir Aujesky Division of General Internal Medicine, Bern University Hospital, Bern, Switzerland 20 November 2013