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A Comparison of Patients Diagnosed With Pulmonary Embolism Who Are ≥65 Years With Patients <65 Years
A Comparison of Patients Diagnosed With Pulmonary Embolism Who Are ‡65 Years With Patients <65 Years Philip Cefalo, MDa,b, Ido Weinberg, MDc, Beau M. Hawkins, MDd, Praveen Hariharan, MBBS, MPHb, Ikenna Okechukwu, MDb, Blair A. Parry, BAb, Yuchiao Chang, PhDe, Rachel Rosovsky, MD, MPHb,f, Shan W. Liu, MD, SDb, Michael R. Jaff, DOc, and Christopher Kabrhel, MD, MPHb,g,* Recent studies have highlighted differences in how older patients respond to high-risk pulmonary embolism (PE) and treatment. However, guidelines for PE risk stratification and treatment are not based on age, and data are lacking for older patients. We characterized the impact of age on clinical features, risk stratification, treatment, and outcomes in a sample of patients with PE in the emergency department. We performed an observational cohort study of 547 consecutive patients with PE in the emergency department from 2005 to 2011 in an urban tertiary hospital. We used bivariate proportions and multivariable logistic regression to compare clinical presentation, risk category, treatment, and outcomes in patients ‡65 years with those <65 years. The mean age was 58 – 17 years, 276 (50%) were women, and 210 (38%) were ‡65 years. PE was more severe in patients ‡65 years (massive 14% vs 5%, submassive 48% vs 25%, and low risk 38% vs 70%, p <0.0001), with submassive PE being the most common presentation in patients ‡65 years. However, subanalysis removing natriuretic peptides from the definition of submassive PE negated this finding. Treatment with parenteral anticoagulation (88% vs 90%, p [ 0.32), thrombolytic therapy (5% vs 4%, p [ 0.87), and inferior vena cava filter (4% vs 4%, p [ 0.73) were similar among age groups. Patients ‡65 years had higher 30-day mortality (11% vs 3%, p <0.001). In conclusion, patients ‡65 years present with more severe PE and have higher mortality, although treatment patterns were similar to younger patients. Age-specific guideline definitions of submassive PE may better identify high-risk patients. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-) Pulmonary embolism (PE) is a leading cause of morbidity and death.1 Older patients have a higher incidence of PE and higher PE-related morbidity and mortality than younger patients.2e8 Guidelines recommend risk-stratifying patients with PE into low risk and submassive and massive categories based on biomarker, radiographic, echocardiographic, and electrocardiographic parameters and suggest basing triage and treatment decisions on these categories.9,10 Recent studies have identified older patients as being at higher risk from the treatment of PE, but few previous studies have focused on PE in patients 65 years, so guideline definitions of submassive and massive PEs do not differ for older patients.9,11,12
a Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, Massachusetts; bCenter for Vascular Emergencies, Department of Emergency Medicine and cDivision of Cardiology and Vascular Medicine, Department of Medicine, The Institute for Heart, Vascular and Stroke Care, Massachusetts General Hospital, Boston, Massachusetts; dCardiovascular Diseases Section, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; eDepartment of Medicine and fDivision of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and gThe Institute for Heart, Vascular, and Stroke Care, Massachusetts General Hospital, Boston, Massachusetts. Manuscript received October 7, 2014; revised manuscript received and accepted December 3, 2014. See page 5 for disclosure information. *Corresponding author: Tel: (617) 726-5824; fax: (617) 724-0917. E-mail address: [email protected] (C. Kabrhel).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.12.025
However, biomarkers and other cardiac parameters are known to change with age, and these changes may decrease the accuracy of risk stratification in patients 65 years.13e15 Recent studies validating age-specific biomarker interpretation support this.16 We, therefore, studied the impact of age on PE risk stratification, clinical features, treatment, and outcomes in patients with PE in the emergency department (ED). Methods We analyzed data from a single-center, observational study performed at a tertiary referral hospital with an annual ED volume of 95,000 patient visits. For the purposes of this analysis, patients from 2 cohorts were grouped. The first was a prospective cohort of 298 enrolled consecutive patients diagnosed with acute PE in the ED from October 2008 to December 2011, and the second was a retrospective cohort of 249 consecutive patients diagnosed with acute PE in the ED from May 2005 to April 2008. The same data form and definitions were used to collect data from both cohorts. Further details regarding the design and methodology of both studies have been previously published.17 Adult patients (age >17 years) were eligible for this study. PE was defined as (a) a filling defect in a pulmonary artery consistent with thromboembolism on computed tomographic pulmonary angiography, (b) a high probability ventilation perfusion (V/Q) lung scan, and/or (c) a lower extremity venous duplex ultrasound or computed tomographic venogram demonstrating deep venous thrombosis in association www.ajconline.org
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Table 1 Cohort clinical features stratified by age Variable
Table 2 Pulmonary embolism severity, treatment and patient outcomes Age<65 years (N¼337)
Age65 years (N¼210)
P value
Age (years)* 4712 757 <.0001 Female 161 (48%) 115 (55%) .11 White 275 (82%) 186 (89%) .029 Coronary artery disease 18 (5%) 36 (17%) <.0001 Congestive heart failure 14 (4%) 17 (8%) .054 Left ventricular ejection fraction <35% 6 (2%) 3 (1%) .76 Renal insufficiency 1 (<1%) 8 (4%) .002 Chronic obstructive pulmonary disease 7 (2%) 27 (13%) <.0001 Cerebrovascular disease 15 (4%) 15 (7%) .18 Prior deep vein thrombosis or 35 (19%) 19 (16%) .50 pulmonary embolism† Recent immobilization† 37 (20%) 33 (28%) .12 Recent immobilization only related to 21 (12%) 5 (4%) .029 travel† All malignancy 96 (28%) 94 (45%) .0001 Active malignancy: under treatment or 60 (18%) 48 (23%) .15 metastatic Highest heart rate (beats per minute)* 9620 9721 .73 Lowest systolic blood pressure 11318 11326 .95 (mm Hg)* Tachypnea (respiratory rate 20 264 (78%) 176 (84%) .081 breaths per minute) Hypoxia (oxygen saturation <90%) 18 (5%) 24 (11%) .009 Atrial fibrillation/flutter on 7 (2%) 19 (9%) .0002 electrocardiogram * Mean standard deviation. † Data available in the prospective cohort only.
with PE symptoms, when the treating clinician confirmed that the test was performed to evaluate suspected PE, not isolated deep vein thrombosis. Patients were eligible for enrollment if they were diagnosed with PE within 24 hours after registering in the ED. Patients transferred from outside EDs or clinics with a diagnosis of PE were eligible for enrollment until 24 hours after their outside hospital radiographic procedure. This study complies with the ethical rules for human experimentation that are stated in the Declaration of Helsinki,18 including approval of an institutional review board and informed consent obtained from all enrolled patients. We collected demographics, co-morbid illnesses, ED vital signs, laboratory results, radiological findings, ED treatment, disposition, and selected outcome measures including admission to intensive care unit, “major bleeding,” and 5-day and 30-day mortality for each enrolled patient. Biomarker (troponin-T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP], D-dimer) and imaging studies were performed at the discretion of the treating physician. Only biomarkers performed within 24 hours of diagnosis were included. The results of echocardiograms performed within 3 days of diagnosis were included. We also collected blood samples from enrolled patients within 24 hours of PE diagnosis and used these to perform biomarker analysis when results were not available clinically. Using this combination of tests, >90% of subjects had a complete panel of biomarkers available for analysis. We also collected data
Variable
Age<65 years (n¼337)
Measures of Pulmonary Embolism Severity: Pulmonary embolism severity index* 7733 Troponin T 0.1 ng/ml 12 (4%) NT-proBNP >500 pg/ml 45 (13%) Right ventricular strain on 38 (11%) electrocardiogram Right ventricular strain on 30 (9%) trans-thoracic echocardiogram Central pulmonary embolism on 155 (46%) computed tomography pulmonary angiography 246 (73%) Multiple pulmonary emboli on computed tomography pulmonary angiography Pulmonary Embolism Severity Category: Low-risk pulmonary embolism 237 (70%) Submassive pulmonary embolism 84 (25%) Massive pulmonary embolism 16 (5%) Treatment: Anticoagulation† 304 (90%) Thrombolysis 15 (4%) Inferior vena cava filter 15 (4%) Outcomes: Admission to intensive care unit 22 (7%) Major bleeding 6 (2%) In-hospital mortalityz 0 (<1%) 30-day mortality 9 (3%)
Age65 years (n¼210)
P value
11934 <.0001 18 (9%) .012 95 (45%) <.0001 30 (14%) .30 31 (15%)
.034
101 (48%)
.63
153 (73%)
.97
<.0001 79 (38%) 101 (48%) 30 (14%) 185 (88%) 10 (5%) 8 (4%) 22 8 2 23
.32 .87 .73
(10%) .099 (4%) .14 (1%) .073 (11%) <.0001
NT-proBNP ¼ N-terminal brain natriuretic peptide. * Mean Standard deviation. † Anticoagulation started in the emergency department. z In-hospital mortality defined as within 5 days of emergency department registration.
necessary to define the Pulmonary Embolism Severity Index, which is a validated clinical score designed to identify patients at risk for 30-day all-cause mortality after acute PE.19,20 We divided our population using an age cutoff of 65 years, as used by the World Health Organization.21 “Massive PE,” “submassive PE,” and “low-risk PE” were defined according to the guidelines of the American Heart Association.9 Massive PE was defined as PE with systolic arterial hypotension (systolic blood pressure <90 mm Hg) and was based on lowest recorded ED blood pressure. Submassive PE was defined as PE with normal blood pressure (systolic blood pressure 90 mm Hg) plus evidence of right ventricular (RV) dysfunction or “myocardial necrosis.” “RV dysfunction” was defined based on electrocardiogram (RsR in V1; right bundle branch block or ST-segment elevation in leads V1, V2, and V3; ST-segment depression in leads V1, V2, and V3; or Twave inversion in leads V1, V2, and V3), echocardiogram (RV dilatation, hypokinesis, or bowing of the intraventricular septum), or NT-proBNP >500 pg/ml. Myocardial necrosis was defined as a troponin T >0.01 ng/ml.9 Low-risk PE was defined as PE with normal blood pressure and no evidence of RV dysfunction.9 To facilitate analysis, we also combined massive and submassive PE into a single category called “severe PE.” “Recent immobilization” was defined as a hospitalization
Miscellaneous/Comparing Pulmonary Embolism in Younger and Older Patients
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from the definition of submassive PE.13,23 We also performed a sensitivity analysis comparing patients 80 years with those <80 years. A 2-sided p value of 0.05 was considered as statistically significant. Analyses were conducted using SAS 9.3 (The SAS Institute, Inc., Cary, North Carolina). Results
Figure 1. PE severity in patients 65 and <65 years and younger patients; y axis represents percentage of patients. MPE ¼ massive pulmonary embolism, SMPE ¼ submassive pulmonary embolism.
Table 3 Multivariable analysis of predictors of massive/submassive pulmonary embolism Variable Age ‡65 years Male gender Coronary artery disease Congestive heart failure Renal insufficiency Lung disease Cerebrovascular disease Malignancy: under treatment or metastatic Atrial fibrillation/flutter
Odds Ratio
95% CI
P value
3.50 0.97 1.45 3.96 2.72 1.28 0.93 0.54
2.36-5.19 0.66-1.42 0.76-2.79 1.55-10.11 0.52-14.16 0.78-2.09 0.40-2.14 0.33-0.88
<.0001 .86 .26 .004 .23 .33 .86 .001
6.02
1.91-18.94
0.002
Note: Immobilization was not included in the multivariate analysis because these data were not available in the retrospective dataset.
lasting 3 days, surgery, leg trauma (or in a cast), or other bedbound state within the last 30 days. “Recent travel” was defined as having duration of 6 hours and occurring within the last 30 days. Major bleeding was defined as intracranial, gastrointestinal, or retroperitoneal bleeding or any bleeding requiring a transfusion of 2 units of packed red blood cells.1,11 We followed patients daily for 5 days while in the hospital and for 30 days after PE using a validated combination of telephone calls and medical record review.22 In our primary analysis, we compared clinical features, PE risk category, treatment, and outcomes across 2 age groups: patients <65 years and those 65 years. We present continuous variables as mean SD and categorical variables as percentages (%). We used Student t tests to compare continuous variables and chi-square tests to compare categorical variables. We performed both multivariable logistic regression and a propensity analysis to determine the association between age 65 years and PE severity, controlling for a prespecified list of potential confounders (gender, coronary artery disease, congestive heart failure, renal insufficiency, lung disease, cerebrovascular disease, active malignancy, and atrial fibrillation/flutter). NT-proBNP increases with age and including NT-proBNP in our definition of submassive PE could influence our results, so we performed a sensitivity analysis omitting NT-proBNP
Overall, the cohort consisted of 547 patients, 298 (54%) from the prospective cohort and 249 (46%) from the retrospective cohort. There were no significant demographic differences between the prospective and retrospective cohorts. The cohort mean age was 58 17 years. Two hundred seventy-six patients (50%) were women, three hundred thirty-seven (62%) were <65 years, 210 were 65 years (38%), and sixty-five patients (12%) were 80 years. The mean age of patients in the <65-year-old group was 47 12 years; those in the 65-year-old group was 75 7 years; and those in the 80-year-old group was 84 4 years. Patients 65 years were more likely to have a history of co-morbid conditions and more likely to present with hypoxemia (Table 1). Presenting clinical features were otherwise similar between groups. Patients 65 years had a higher prevalence of most laboratory and imaging measures of severe PE compared with patients <65 years (Table 2) and accordingly were more likely to be categorized as having higher PE severity on presentation (massive 14% vs 5%, submassive 48% vs 25%, and low risk 38% vs 70%, p <0.0001; Figure 1). Patients 65 years were most likely to present with submassive PE, whereas patients <65 years were most likely to present with low-risk PE. Among all patients, 73 had submassive PE based on NT-proBNP alone (13% of enrolled and 40% of submassive PE). In patients 65 years, 52 had submassive PE based on NT-proBNP alone (25% of enrolled and 52% of submassive PE), whereas 21 patients <65 years had submassive PE based on NT-proBNP alone (6% of enrolled and 25% of submassive PE). In 140 patients with elevated NT-proBNP, 20 (14%) had a history of congestive heart failure and 6 (4%) had a previously documented left ventricular ejection fraction <35%. The mean Pulmonary Embolism Severity Index score, which includes age, was also higher in patients 65 years (119 vs 77, p 0.0001). On multivariable analysis, age 65 years was an independent predictor of PE severity (Table 3). Similarly, on propensity analysis (matched on coronary artery disease, congestive heart failure, renal insufficiency, lung disease, cerebrovascular disease, active malignancy, atrial fibrillation/ flutter), patients 65 years were more likely to have massive/ submassive PE (p <0.001). In our subanalysis of patients with severe (the combination of massive and submassive) PE, patients 65 years were more likely than patients <65 years to have an elevated NT-proBNP (73% vs 45%, p <0.0001) but were not more likely to have other markers of PE severity (data not shown). Patients were treated according to the hospital standard with intravenous unfractionated heparin or lowemolecular weight heparin, followed by warfarin therapy in the outpatient setting. There were no differences in the proportion of patients whose parenteral anticoagulation was initiated in the ED or those receiving thrombolytic therapy or inferior vena
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cava (IVC) filter placement (Table 2). In patients with severe PE, there was also no difference in treatment pattern between patients 65 years and those <65 years. Initiation of parenteral anticoagulation in the ED (89% vs 87%, p ¼ 0.72), thrombolytic therapy (6% vs 11%, p ¼ 0.18), and IVC filter placement (6% vs 9%, p ¼ 0.43) were also similar across age groups in patients with severe PE. Patients 65 years with PE had higher all-cause 30-day mortality compared with those <65 years (11% vs 3%, p <0.0001; Table 2). In patients with severe PE, patients 65 years had higher 30-day mortality compared with those <65 years (15% vs 4%, p ¼ 0.008). However, there was no difference in 30-day mortality across age groups in patients who presented with low-risk PE (5% vs 2%, p ¼ 0.17). Because patients 65 years with severe PE were more likely to have an elevated NT-proBNP, we performed a sensitivity analysis to determine if omitting NT-proBNP from the definition of submassive PE changed our results. When we removed NT-proBNP from the definition of submassive PE, there was no longer a difference in the proportion of submassive PE between patients 65 years and those <65 years (23% vs 19%, p ¼ 0.19). However, In patients with severe PE, patients 65 years were more likely to have massive PE compared with those <65 years (38% vs 20%, p ¼ 0.014). Accordingly, the proportion of severe (submassive or massive) PE remained higher in patients 65 years (38% vs 23%, p ¼ 0.0004), and the overall trend toward more severe PE in patients 65 years remained significant (p <0.0001), with NT-proBNP taken out of the definition of submassive PE. In a multivariable analysis when the definition of severe PE did not include NT-proBNP, age 65 years remained an independent predictor of severe PE (odds ratio ¼ 1.92, confidence interval ¼ 1.28 to 2.86, p ¼ 0.002). A statistical analysis comparing patients 80 years with those <80 years was consistent with the findings of our primary analysis, with patients 80 years presenting with more severe PE compared with those <80 years (massive PE 12% vs 8%, submassive PE 65% vs 30%, low risk 23% vs 62%, p <0.0001; Figure 1). In patients with severe PE, patients 80 years were more likely to have an elevated NT-proBNP (84% vs 54%, p ¼ 0.0001), with no difference in the other markers of PE severity. Discussion In our study of 547 patients with PE in the ED, patients 65 years present with more severe PE than those <65 years, and age 65 years is an independent predictor of severe PE. However, patients 65 years do not receive more aggressive PE treatment. This is the first large contemporary study to examine the risk stratification, treatment, and outcomes of patients 65 years diagnosed with PE in the ED. Our findings add to previous studies of PE in older patients. In 644 older patients with PE and deep vein thrombosis in the SWIss Venous ThromboEmbolism Registry (SWIVTER), there was a nonsignificant suggestion of a higher rate of massive PE in patients 65 years (8% vs 4%, p ¼ 0.07), with no difference in the use of thrombolysis, catheter intervention, or surgery.20 These results are consistent with ours. However, our analysis also included submassive PE,
which is the most common PE presentation in patients 65 years and 80 years (48% and 65%, respectively). This has not been previously described. Despite our finding that patients 65 years with PE are more likely to have submassive PE than younger patients, we found that NT-proBNP elevation accounts for much of the increased prevalence of submassive PE in older patients. Natriuretic peptide levels are known to increase with advancing age and with co-morbid illnesses that are common in older patients and, therefore, may be elevated even without acute RV dysfunction.13 For example, in our study, younger patients with atrial fibrillation were more likely to have a normal NT-proBNP (<500 ng/ml; 71% vs 29%), whereas older patients with atrial fibrillation were more likely to have an elevated NT-proBNP (79% vs 21%). These findings are consistent with previous studies that show that NT-proBNP elevation is independently associated with older age.13,23 Given this, we were concerned that the inclusion of NT-proBNP in the definition of submassive PE (as recommended by the American Heart Association guidelines) could artificially inflate the prevalence of submassive PE in older patients. When we removed NT-proBNP from the definition of submassive PE, patients 65 years were no longer more likely to present with submassive PE, although the trend toward more severe PE in patients 65 years remained significant because of the higher proportion of massive PE in this group. Previous studies demonstrating the prognostic value of natriuretic peptides in PE, on which guideline definitions are based, did not specifically evaluate patients 65 years.12,24,25 The few studies that have examined natriuretic peptides for PE risk stratification in older patients question their reliability and suggest that a higher cutoff may be needed.26,27 Our results suggest that natriuretic peptides should be used cautiously when assessing PE severity in patients 65 years. The definition of submassive PE in older patients may need to be revised. This is especially important as recent data support the use of thrombolysis in submassive PE but with an increased risk of bleeding in older patients.11 We found no significant difference in the utilization of aggressive therapies (e.g., thrombolysis) between patients 65 years and those <65 years presenting with PE, despite increased PE severity in patients 65 years. Although current American College of Chest Physicians guidelines for management of acute PE do not incorporate age,10 it is likely that clinicians withhold aggressive therapy because of greater concern about bleeding risk associated with fibrinolysis in older patients.11,28 Patients 65 years with severe PE in our study had higher 30-day mortality (14% vs 4%, p ¼ 0.011) than younger patients. Although this could reflect the association between age and mortality, we did not see the same difference in patients with low-risk PE. This suggests that PE severity may contribute to the increased mortality in patients 65 years with PE. Our results are consistent with results from the SWIVTER registry, in which older patients had a higher rate of in-hospital death and major bleeding.29 There are several limitations to consider in the interpretation of these results. Patients diagnosed >24 hours into their hospitalization were excluded from our study, so our results may not apply to inpatient PE diagnoses or patients in the ED with delayed diagnosis. We did not specifically report
Miscellaneous/Comparing Pulmonary Embolism in Younger and Older Patients
co-presentation of PE and other conditions that may result in hemodynamic instability. To assess whether the effect of age on massive/submassive PE was confounded by co-morbid illness, we performed multivariable logistic regression and propensity analysis. However, it is possible that there were confounders of the relation between age and massive/ submassive PE that we did not include in our models. The finding of our multivariable analysis that active malignancy is negatively associated with severe PE is counterintuitive and may be because of the chance or unmeasured confounders. This requires further exploration. There was a trend toward a higher rate of congestive heart failure and a significantly higher rate of atrial fibrillation in patients 65 years (Table 1). This might be associated with higher levels of NT-proBNP in patients 65 years. Finally, we did not collect information on contraindications to thrombolytic therapy, which are likely higher in patients 65 years. This may partially explain the discordance between PE severity and treatment aggressiveness in this population. Our findings suggest that a more restrictive guideline definition for submassive PE may be needed to accurately identify high-risk patients 65 years. Studies of age-specific PE risk stratification, and specifically the use of NTproBNP, are needed.
10.
11.
12.
13. 14.
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26. Ray P, Maziere F, Medimagh S, Lefort Y, Arthaud M, Duguet A, Teixeira A, Riou B. Evaluation of B-type natriuretic peptide to predict complicated pulmonary embolism in patients aged 65 years and older: brief report. Am J Emerg Med 2006;24:603e607. 27. Dores H, Fonseca C, Leal S, Rosário I, Abecasis J, Monge J, Correia MJ, Bronze L, Leitão A, Arroja I, Aleixo A, Silva A. NT-proBNP for risk stratification of pulmonary embolism. Rev Port Cardiol 2011;30: 881e886.
28. Mikkola KM, Patel SR, Parker JA, Grodstein F, Goldhaber SZ. Increasing age is a major risk factor for hemorrhagic complications after pulmonary embolism thrombolysis. Am Heart J 1997;134:69e72. 29. Spirk D, Husmann M, Hayoz D, Baldi T, Frauchiger B, Engelberger R, Amann-Vesti B, Baumgartner I, Kucher N. Predictors of in-hospital mortality in elderly patients with acute venous thrombo-embolism: the SWIss Venous ThromboEmbolism Registry (SWIVTER). Eur Heart J 2012;33:921e926.
a Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, Massachusetts; bCenter for Vascular Emergencies, Department of Emergency Medicine and cDivision of Cardiology and Vascular Medicine, Department of Medicine, The Institute for Heart, Vascular and Stroke Care, Massachusetts General Hospital, Boston, Massachusetts; dCardiovascular Diseases Section, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; eDepartment of Medicine and fDivision of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and gThe Institute for Heart, Vascular, and Stroke Care, Massachusetts General Hospital, Boston, Massachusetts. Manuscript received October 7, 2014; revised manuscript received and accepted December 3, 2014. See page 5 for disclosure information. *Corresponding author: Tel: (617) 726-5824; fax: (617) 724-0917. E-mail address: [email protected] (C. Kabrhel).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.12.025
However, biomarkers and other cardiac parameters are known to change with age, and these changes may decrease the accuracy of risk stratification in patients 65 years.13e15 Recent studies validating age-specific biomarker interpretation support this.16 We, therefore, studied the impact of age on PE risk stratification, clinical features, treatment, and outcomes in patients with PE in the emergency department (ED). Methods We analyzed data from a single-center, observational study performed at a tertiary referral hospital with an annual ED volume of 95,000 patient visits. For the purposes of this analysis, patients from 2 cohorts were grouped. The first was a prospective cohort of 298 enrolled consecutive patients diagnosed with acute PE in the ED from October 2008 to December 2011, and the second was a retrospective cohort of 249 consecutive patients diagnosed with acute PE in the ED from May 2005 to April 2008. The same data form and definitions were used to collect data from both cohorts. Further details regarding the design and methodology of both studies have been previously published.17 Adult patients (age >17 years) were eligible for this study. PE was defined as (a) a filling defect in a pulmonary artery consistent with thromboembolism on computed tomographic pulmonary angiography, (b) a high probability ventilation perfusion (V/Q) lung scan, and/or (c) a lower extremity venous duplex ultrasound or computed tomographic venogram demonstrating deep venous thrombosis in association www.ajconline.org
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Table 1 Cohort clinical features stratified by age Variable
Table 2 Pulmonary embolism severity, treatment and patient outcomes Age<65 years (N¼337)
Age65 years (N¼210)
P value
Age (years)* 4712 757 <.0001 Female 161 (48%) 115 (55%) .11 White 275 (82%) 186 (89%) .029 Coronary artery disease 18 (5%) 36 (17%) <.0001 Congestive heart failure 14 (4%) 17 (8%) .054 Left ventricular ejection fraction <35% 6 (2%) 3 (1%) .76 Renal insufficiency 1 (<1%) 8 (4%) .002 Chronic obstructive pulmonary disease 7 (2%) 27 (13%) <.0001 Cerebrovascular disease 15 (4%) 15 (7%) .18 Prior deep vein thrombosis or 35 (19%) 19 (16%) .50 pulmonary embolism† Recent immobilization† 37 (20%) 33 (28%) .12 Recent immobilization only related to 21 (12%) 5 (4%) .029 travel† All malignancy 96 (28%) 94 (45%) .0001 Active malignancy: under treatment or 60 (18%) 48 (23%) .15 metastatic Highest heart rate (beats per minute)* 9620 9721 .73 Lowest systolic blood pressure 11318 11326 .95 (mm Hg)* Tachypnea (respiratory rate 20 264 (78%) 176 (84%) .081 breaths per minute) Hypoxia (oxygen saturation <90%) 18 (5%) 24 (11%) .009 Atrial fibrillation/flutter on 7 (2%) 19 (9%) .0002 electrocardiogram * Mean standard deviation. † Data available in the prospective cohort only.
with PE symptoms, when the treating clinician confirmed that the test was performed to evaluate suspected PE, not isolated deep vein thrombosis. Patients were eligible for enrollment if they were diagnosed with PE within 24 hours after registering in the ED. Patients transferred from outside EDs or clinics with a diagnosis of PE were eligible for enrollment until 24 hours after their outside hospital radiographic procedure. This study complies with the ethical rules for human experimentation that are stated in the Declaration of Helsinki,18 including approval of an institutional review board and informed consent obtained from all enrolled patients. We collected demographics, co-morbid illnesses, ED vital signs, laboratory results, radiological findings, ED treatment, disposition, and selected outcome measures including admission to intensive care unit, “major bleeding,” and 5-day and 30-day mortality for each enrolled patient. Biomarker (troponin-T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP], D-dimer) and imaging studies were performed at the discretion of the treating physician. Only biomarkers performed within 24 hours of diagnosis were included. The results of echocardiograms performed within 3 days of diagnosis were included. We also collected blood samples from enrolled patients within 24 hours of PE diagnosis and used these to perform biomarker analysis when results were not available clinically. Using this combination of tests, >90% of subjects had a complete panel of biomarkers available for analysis. We also collected data
Variable
Age<65 years (n¼337)
Measures of Pulmonary Embolism Severity: Pulmonary embolism severity index* 7733 Troponin T 0.1 ng/ml 12 (4%) NT-proBNP >500 pg/ml 45 (13%) Right ventricular strain on 38 (11%) electrocardiogram Right ventricular strain on 30 (9%) trans-thoracic echocardiogram Central pulmonary embolism on 155 (46%) computed tomography pulmonary angiography 246 (73%) Multiple pulmonary emboli on computed tomography pulmonary angiography Pulmonary Embolism Severity Category: Low-risk pulmonary embolism 237 (70%) Submassive pulmonary embolism 84 (25%) Massive pulmonary embolism 16 (5%) Treatment: Anticoagulation† 304 (90%) Thrombolysis 15 (4%) Inferior vena cava filter 15 (4%) Outcomes: Admission to intensive care unit 22 (7%) Major bleeding 6 (2%) In-hospital mortalityz 0 (<1%) 30-day mortality 9 (3%)
Age65 years (n¼210)
P value
11934 <.0001 18 (9%) .012 95 (45%) <.0001 30 (14%) .30 31 (15%)
.034
101 (48%)
.63
153 (73%)
.97
<.0001 79 (38%) 101 (48%) 30 (14%) 185 (88%) 10 (5%) 8 (4%) 22 8 2 23
.32 .87 .73
(10%) .099 (4%) .14 (1%) .073 (11%) <.0001
NT-proBNP ¼ N-terminal brain natriuretic peptide. * Mean Standard deviation. † Anticoagulation started in the emergency department. z In-hospital mortality defined as within 5 days of emergency department registration.
necessary to define the Pulmonary Embolism Severity Index, which is a validated clinical score designed to identify patients at risk for 30-day all-cause mortality after acute PE.19,20 We divided our population using an age cutoff of 65 years, as used by the World Health Organization.21 “Massive PE,” “submassive PE,” and “low-risk PE” were defined according to the guidelines of the American Heart Association.9 Massive PE was defined as PE with systolic arterial hypotension (systolic blood pressure <90 mm Hg) and was based on lowest recorded ED blood pressure. Submassive PE was defined as PE with normal blood pressure (systolic blood pressure 90 mm Hg) plus evidence of right ventricular (RV) dysfunction or “myocardial necrosis.” “RV dysfunction” was defined based on electrocardiogram (RsR in V1; right bundle branch block or ST-segment elevation in leads V1, V2, and V3; ST-segment depression in leads V1, V2, and V3; or Twave inversion in leads V1, V2, and V3), echocardiogram (RV dilatation, hypokinesis, or bowing of the intraventricular septum), or NT-proBNP >500 pg/ml. Myocardial necrosis was defined as a troponin T >0.01 ng/ml.9 Low-risk PE was defined as PE with normal blood pressure and no evidence of RV dysfunction.9 To facilitate analysis, we also combined massive and submassive PE into a single category called “severe PE.” “Recent immobilization” was defined as a hospitalization
Miscellaneous/Comparing Pulmonary Embolism in Younger and Older Patients
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from the definition of submassive PE.13,23 We also performed a sensitivity analysis comparing patients 80 years with those <80 years. A 2-sided p value of 0.05 was considered as statistically significant. Analyses were conducted using SAS 9.3 (The SAS Institute, Inc., Cary, North Carolina). Results
Figure 1. PE severity in patients 65 and <65 years and younger patients; y axis represents percentage of patients. MPE ¼ massive pulmonary embolism, SMPE ¼ submassive pulmonary embolism.
Table 3 Multivariable analysis of predictors of massive/submassive pulmonary embolism Variable Age ‡65 years Male gender Coronary artery disease Congestive heart failure Renal insufficiency Lung disease Cerebrovascular disease Malignancy: under treatment or metastatic Atrial fibrillation/flutter
Odds Ratio
95% CI
P value
3.50 0.97 1.45 3.96 2.72 1.28 0.93 0.54
2.36-5.19 0.66-1.42 0.76-2.79 1.55-10.11 0.52-14.16 0.78-2.09 0.40-2.14 0.33-0.88
<.0001 .86 .26 .004 .23 .33 .86 .001
6.02
1.91-18.94
0.002
Note: Immobilization was not included in the multivariate analysis because these data were not available in the retrospective dataset.
lasting 3 days, surgery, leg trauma (or in a cast), or other bedbound state within the last 30 days. “Recent travel” was defined as having duration of 6 hours and occurring within the last 30 days. Major bleeding was defined as intracranial, gastrointestinal, or retroperitoneal bleeding or any bleeding requiring a transfusion of 2 units of packed red blood cells.1,11 We followed patients daily for 5 days while in the hospital and for 30 days after PE using a validated combination of telephone calls and medical record review.22 In our primary analysis, we compared clinical features, PE risk category, treatment, and outcomes across 2 age groups: patients <65 years and those 65 years. We present continuous variables as mean SD and categorical variables as percentages (%). We used Student t tests to compare continuous variables and chi-square tests to compare categorical variables. We performed both multivariable logistic regression and a propensity analysis to determine the association between age 65 years and PE severity, controlling for a prespecified list of potential confounders (gender, coronary artery disease, congestive heart failure, renal insufficiency, lung disease, cerebrovascular disease, active malignancy, and atrial fibrillation/flutter). NT-proBNP increases with age and including NT-proBNP in our definition of submassive PE could influence our results, so we performed a sensitivity analysis omitting NT-proBNP
Overall, the cohort consisted of 547 patients, 298 (54%) from the prospective cohort and 249 (46%) from the retrospective cohort. There were no significant demographic differences between the prospective and retrospective cohorts. The cohort mean age was 58 17 years. Two hundred seventy-six patients (50%) were women, three hundred thirty-seven (62%) were <65 years, 210 were 65 years (38%), and sixty-five patients (12%) were 80 years. The mean age of patients in the <65-year-old group was 47 12 years; those in the 65-year-old group was 75 7 years; and those in the 80-year-old group was 84 4 years. Patients 65 years were more likely to have a history of co-morbid conditions and more likely to present with hypoxemia (Table 1). Presenting clinical features were otherwise similar between groups. Patients 65 years had a higher prevalence of most laboratory and imaging measures of severe PE compared with patients <65 years (Table 2) and accordingly were more likely to be categorized as having higher PE severity on presentation (massive 14% vs 5%, submassive 48% vs 25%, and low risk 38% vs 70%, p <0.0001; Figure 1). Patients 65 years were most likely to present with submassive PE, whereas patients <65 years were most likely to present with low-risk PE. Among all patients, 73 had submassive PE based on NT-proBNP alone (13% of enrolled and 40% of submassive PE). In patients 65 years, 52 had submassive PE based on NT-proBNP alone (25% of enrolled and 52% of submassive PE), whereas 21 patients <65 years had submassive PE based on NT-proBNP alone (6% of enrolled and 25% of submassive PE). In 140 patients with elevated NT-proBNP, 20 (14%) had a history of congestive heart failure and 6 (4%) had a previously documented left ventricular ejection fraction <35%. The mean Pulmonary Embolism Severity Index score, which includes age, was also higher in patients 65 years (119 vs 77, p 0.0001). On multivariable analysis, age 65 years was an independent predictor of PE severity (Table 3). Similarly, on propensity analysis (matched on coronary artery disease, congestive heart failure, renal insufficiency, lung disease, cerebrovascular disease, active malignancy, atrial fibrillation/ flutter), patients 65 years were more likely to have massive/ submassive PE (p <0.001). In our subanalysis of patients with severe (the combination of massive and submassive) PE, patients 65 years were more likely than patients <65 years to have an elevated NT-proBNP (73% vs 45%, p <0.0001) but were not more likely to have other markers of PE severity (data not shown). Patients were treated according to the hospital standard with intravenous unfractionated heparin or lowemolecular weight heparin, followed by warfarin therapy in the outpatient setting. There were no differences in the proportion of patients whose parenteral anticoagulation was initiated in the ED or those receiving thrombolytic therapy or inferior vena
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cava (IVC) filter placement (Table 2). In patients with severe PE, there was also no difference in treatment pattern between patients 65 years and those <65 years. Initiation of parenteral anticoagulation in the ED (89% vs 87%, p ¼ 0.72), thrombolytic therapy (6% vs 11%, p ¼ 0.18), and IVC filter placement (6% vs 9%, p ¼ 0.43) were also similar across age groups in patients with severe PE. Patients 65 years with PE had higher all-cause 30-day mortality compared with those <65 years (11% vs 3%, p <0.0001; Table 2). In patients with severe PE, patients 65 years had higher 30-day mortality compared with those <65 years (15% vs 4%, p ¼ 0.008). However, there was no difference in 30-day mortality across age groups in patients who presented with low-risk PE (5% vs 2%, p ¼ 0.17). Because patients 65 years with severe PE were more likely to have an elevated NT-proBNP, we performed a sensitivity analysis to determine if omitting NT-proBNP from the definition of submassive PE changed our results. When we removed NT-proBNP from the definition of submassive PE, there was no longer a difference in the proportion of submassive PE between patients 65 years and those <65 years (23% vs 19%, p ¼ 0.19). However, In patients with severe PE, patients 65 years were more likely to have massive PE compared with those <65 years (38% vs 20%, p ¼ 0.014). Accordingly, the proportion of severe (submassive or massive) PE remained higher in patients 65 years (38% vs 23%, p ¼ 0.0004), and the overall trend toward more severe PE in patients 65 years remained significant (p <0.0001), with NT-proBNP taken out of the definition of submassive PE. In a multivariable analysis when the definition of severe PE did not include NT-proBNP, age 65 years remained an independent predictor of severe PE (odds ratio ¼ 1.92, confidence interval ¼ 1.28 to 2.86, p ¼ 0.002). A statistical analysis comparing patients 80 years with those <80 years was consistent with the findings of our primary analysis, with patients 80 years presenting with more severe PE compared with those <80 years (massive PE 12% vs 8%, submassive PE 65% vs 30%, low risk 23% vs 62%, p <0.0001; Figure 1). In patients with severe PE, patients 80 years were more likely to have an elevated NT-proBNP (84% vs 54%, p ¼ 0.0001), with no difference in the other markers of PE severity. Discussion In our study of 547 patients with PE in the ED, patients 65 years present with more severe PE than those <65 years, and age 65 years is an independent predictor of severe PE. However, patients 65 years do not receive more aggressive PE treatment. This is the first large contemporary study to examine the risk stratification, treatment, and outcomes of patients 65 years diagnosed with PE in the ED. Our findings add to previous studies of PE in older patients. In 644 older patients with PE and deep vein thrombosis in the SWIss Venous ThromboEmbolism Registry (SWIVTER), there was a nonsignificant suggestion of a higher rate of massive PE in patients 65 years (8% vs 4%, p ¼ 0.07), with no difference in the use of thrombolysis, catheter intervention, or surgery.20 These results are consistent with ours. However, our analysis also included submassive PE,
which is the most common PE presentation in patients 65 years and 80 years (48% and 65%, respectively). This has not been previously described. Despite our finding that patients 65 years with PE are more likely to have submassive PE than younger patients, we found that NT-proBNP elevation accounts for much of the increased prevalence of submassive PE in older patients. Natriuretic peptide levels are known to increase with advancing age and with co-morbid illnesses that are common in older patients and, therefore, may be elevated even without acute RV dysfunction.13 For example, in our study, younger patients with atrial fibrillation were more likely to have a normal NT-proBNP (<500 ng/ml; 71% vs 29%), whereas older patients with atrial fibrillation were more likely to have an elevated NT-proBNP (79% vs 21%). These findings are consistent with previous studies that show that NT-proBNP elevation is independently associated with older age.13,23 Given this, we were concerned that the inclusion of NT-proBNP in the definition of submassive PE (as recommended by the American Heart Association guidelines) could artificially inflate the prevalence of submassive PE in older patients. When we removed NT-proBNP from the definition of submassive PE, patients 65 years were no longer more likely to present with submassive PE, although the trend toward more severe PE in patients 65 years remained significant because of the higher proportion of massive PE in this group. Previous studies demonstrating the prognostic value of natriuretic peptides in PE, on which guideline definitions are based, did not specifically evaluate patients 65 years.12,24,25 The few studies that have examined natriuretic peptides for PE risk stratification in older patients question their reliability and suggest that a higher cutoff may be needed.26,27 Our results suggest that natriuretic peptides should be used cautiously when assessing PE severity in patients 65 years. The definition of submassive PE in older patients may need to be revised. This is especially important as recent data support the use of thrombolysis in submassive PE but with an increased risk of bleeding in older patients.11 We found no significant difference in the utilization of aggressive therapies (e.g., thrombolysis) between patients 65 years and those <65 years presenting with PE, despite increased PE severity in patients 65 years. Although current American College of Chest Physicians guidelines for management of acute PE do not incorporate age,10 it is likely that clinicians withhold aggressive therapy because of greater concern about bleeding risk associated with fibrinolysis in older patients.11,28 Patients 65 years with severe PE in our study had higher 30-day mortality (14% vs 4%, p ¼ 0.011) than younger patients. Although this could reflect the association between age and mortality, we did not see the same difference in patients with low-risk PE. This suggests that PE severity may contribute to the increased mortality in patients 65 years with PE. Our results are consistent with results from the SWIVTER registry, in which older patients had a higher rate of in-hospital death and major bleeding.29 There are several limitations to consider in the interpretation of these results. Patients diagnosed >24 hours into their hospitalization were excluded from our study, so our results may not apply to inpatient PE diagnoses or patients in the ED with delayed diagnosis. We did not specifically report
Miscellaneous/Comparing Pulmonary Embolism in Younger and Older Patients
co-presentation of PE and other conditions that may result in hemodynamic instability. To assess whether the effect of age on massive/submassive PE was confounded by co-morbid illness, we performed multivariable logistic regression and propensity analysis. However, it is possible that there were confounders of the relation between age and massive/ submassive PE that we did not include in our models. The finding of our multivariable analysis that active malignancy is negatively associated with severe PE is counterintuitive and may be because of the chance or unmeasured confounders. This requires further exploration. There was a trend toward a higher rate of congestive heart failure and a significantly higher rate of atrial fibrillation in patients 65 years (Table 1). This might be associated with higher levels of NT-proBNP in patients 65 years. Finally, we did not collect information on contraindications to thrombolytic therapy, which are likely higher in patients 65 years. This may partially explain the discordance between PE severity and treatment aggressiveness in this population. Our findings suggest that a more restrictive guideline definition for submassive PE may be needed to accurately identify high-risk patients 65 years. Studies of age-specific PE risk stratification, and specifically the use of NTproBNP, are needed.
10.
11.
12.
13. 14.
Disclosures This work was supported by a grant from the Harvard Milton fund, Boston, Massachusetts. This sponsor had no role in study design, data collection or analysis, or in the writing of the report. 1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386e1389. 2. Kniffin WD, Baron JA, Barrett J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861e866. 3. Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933e938. 4. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585e593. 5. Punukollu H, Khan IA, Punukollu G, Gowda RM, Mendoza C, Sacchi TJ. Acute pulmonary embolism in elderly: clinical characteristics and outcome. Int J Cardiol 2005;99:213e216. 6. Bajaj N, Bozarth AL, Guillot J, Kojokittah J, Appalaneni SR, Cestero C, Amankona RK, Pippim JA. Clinical features in patients with pulmonary embolism at a community hospital: analysis of 4 years of data. J Thromb Thrombolysis 2013;37:287e292. 7. Kokturk N, Oguzulgen IK, Demir N, Demirel K, Ekim N. Differences in clinical presentation of pulmonary embolism in older vs younger patients. Circ J 2005;69:981e986. 8. Masotti L, Ray P, Righini M, Le Gal G, Antonelli F, Landini G, Cappelli R, Prisco D, Rottoli P. Pulmonary embolism in the elderly: a review on clinical, instrumental and laboratory presentation. Vasc Health Risk Managament 2008;4:629e636. 9. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis,
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Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123: 1788e1830. Guyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, Crowther M, Vandvik PO, Eikelboom JW, McDonagh MS, Lewis SZ, Gutterman DD, Cook DJ, Schünemann HJ; American College of Chest Physicians. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:53Se70S. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, BeyerWestendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galiè N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; for the PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370: 1402e1411. Sanchez O, Trinquart L, Colombet I, Durieux P, Huisman MV, Chatellier G, Meyer G. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008;29:1569e1577. Redfield M, Rodeheffer R, Jacobsen S, Mahoney D, Bailey K, Burnett J Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:976e982. Fiechter M, Fuchs TA, Gebhard C, Stehli J, Klaeser B, Stahli BE, Manes C, Tanner TC, Gaemperli O, Kaufmann PA. Age-related normal structural and functional ventricular values in cardiac function assessed by magnetic resonance. BMC Med Imaging 2013;13:6. Gruner Svealv B, Fritzon G, Anderson B. Gender and age related differences in left ventricular function and geometry with focus on the long axis. Eur J Echocardiogr 2006;7:298e307. Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, Rutschmann OT, Sanchez O, Jaffrelot M, Trinh-Duc A, Le Gall C, Moustafa F, Principe A, Van Houten AA, Wolde MT, Douma RA, Hazelaar G, Erkens PMG, Van Kralingen KW, Grootenboers MJJH, Durian MF, Cheung YW, Meyer G, Bounameaux H, Huisman MV, Kamphuisen PW, Le Gal G. Age-adjusted d-dimer cutoff levels to rule out pulmonary embolism: the adjust-PE study. JAMA 2014;311: 1117e1124. Hariharan P, Takayesu JK, Kabrhel C. Association between pulmonary embolism severity index (PESI) and short-term clinical deterioration. Thromb Haemost 2011;105:706e711. World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997;277:925e926. Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, Roy PM, Fine MJ. A prediction rule to identify low-risk patients with pulmonary embolism. Arch Intern Med 2006;166:169e175. Aujesky D, Perrier A, Roy PM, Stone RA, Cornuz J, Meyer G, Obrosky DS, Fine MJ. Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism. J Intern Med 2007;261:597e604. World Health Organization, Available at: http://www.who.int/healthinfo/ survey/ageingdefnolder/en/. Accessed on September 15, 2014. Kline JA, Mitchell AM, Runyon MS, Jones AE, Webb WB. Electronic medical record review as a surrogate to telephone follow-up to establish outcome for diagnostic research studies in the emergency department. Acad Emerg Med 2005;12:1127e1133. Wang TJ, Larson MG, Levy D, Leip EP, Benjamin EJ, Wilson PW. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 2002;90:254e258. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008;178:425e430. Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism: a systematic review. Intensive Care Med 2008;34:2147e2156.
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26. Ray P, Maziere F, Medimagh S, Lefort Y, Arthaud M, Duguet A, Teixeira A, Riou B. Evaluation of B-type natriuretic peptide to predict complicated pulmonary embolism in patients aged 65 years and older: brief report. Am J Emerg Med 2006;24:603e607. 27. Dores H, Fonseca C, Leal S, Rosário I, Abecasis J, Monge J, Correia MJ, Bronze L, Leitão A, Arroja I, Aleixo A, Silva A. NT-proBNP for risk stratification of pulmonary embolism. Rev Port Cardiol 2011;30: 881e886.
28. Mikkola KM, Patel SR, Parker JA, Grodstein F, Goldhaber SZ. Increasing age is a major risk factor for hemorrhagic complications after pulmonary embolism thrombolysis. Am Heart J 1997;134:69e72. 29. Spirk D, Husmann M, Hayoz D, Baldi T, Frauchiger B, Engelberger R, Amann-Vesti B, Baumgartner I, Kucher N. Predictors of in-hospital mortality in elderly patients with acute venous thrombo-embolism: the SWIss Venous ThromboEmbolism Registry (SWIVTER). Eur Heart J 2012;33:921e926.