Accuracy of the Wells Clinical Prediction Rule for Pulmonary Embolism in Older Ambulatory Adults Henrike J. Schouten, PhD,*† Geert-Jan Geersing, PhD,* Ruud Oudega, PhD,* Johannes J.M. van Delden, PhD,* Karel G.M. Moons, PhD,* and Huiberdina L. Koek, PhD†
OBJECTIVES: To determine whether the Wells clinical prediction rule for pulmonary embolism (PE), which produces a point score based on clinical features and the likelihood of diagnoses other than PE, combined with normal D-dimer testing can be used to exclude PE in older unhospitalized adults. DESIGN: Prospective cohort study. SETTING: Primary care and nursing homes. PARTICIPANTS: Older adults (≥60) clinically suspected of having a PE (N = 294, mean age 76, 44% residing in a nursing home). MEASUREMENTS: The presence of PE was confirmed using a composite reference standard including computed tomography and 3-month follow-up. The proportion of individuals with an unlikely risk of PE was calculated according to the Wells rule (≤4 points) plus a normal qualitative point-of-care D-dimer test (efficiency) and the presence of symptomatic PE during 3 months of follow-up within these patients (failure rate). RESULTS: Pulmonary embolism occurred in 83 participants (28%). Eighty-five participants had an unlikely risk according to the Wells rule and a normal D-dimer test (efficiency 29%), five of whom experienced a nonfatal PE during 3 months of follow-up (failure rate = 5.9%, 95% confidence interval (CI) = 2.5–13%). According to a refitted diagnostic strategy for older adults, 69 had a low risk of PE (24%), two of whom had PE (failure rate = 2.9%, 95% CI = 0.8–10%). CONCLUSION: The use of the well-known and widely used Wells rule (original or refitted) does not guarantee safe exclusion of PE in older unhospitalized adults with suspected PE. This may lead to discussion among professionals as to whether the original or revised Wells rule is
From the *Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, and †Department of Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands. Address correspondence to Henrike J. Schouten, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Str 6.131, PO Box 85500, Utrecht, 3508GA, the Netherlands. E-mail: [email protected] DOI: 10.1111/jgs.13080
JAGS 62:2136–2141, 2014 © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society
useful for elderly outpatients. J Am Geriatr Soc 62:2136– 2141, 2014.
Key words: pulmonary embolism; elderly; diagnosis; venous thromboembolism; nursing home; D-dimer; geriatric; Wells; clinical decision rule
G
iven the exponential rise of the incidence of venous thromboembolism with increasing age, the majority of (potentially fatal) pulmonary emboli (PEs) occur in older adults.1–3 Although accurately and timely diagnosis of PE can be lifesaving, it is notoriously difficult in elderly adults, in whom clinical symptoms and signs of PE can be subtle or obscured by other cardiac or pulmonary comorbidities.4 Consequently, physicians need to refer many older adults suspected of having a PE to confirm one case. (One in five individuals with suspected PE has confirmed PE.5) This can be burdensome, given that this population is particularly vulnerable to distress resulting from transitions for hospital care.6,7 Diagnostic decision rules—such as the Wells rule combined with D-dimer testing—have been developed to distinguish a subgroup of participants in whom PE can be excluded without referral for imaging examination.8 This exclusion strategy has been extensively validated in primary and hospital care, mainly in younger adults,9,10 but the accuracy of the existing clinical decision rules to exclude PE has never been tested in elderly populations. This is important because a change in setting (e.g., from hospital to nursing home care) results in a different case mix, which may affect the diagnostic accuracy and thus generalizability of decision rules.11–13 Therefore, this prospective study was conducted to assess the accuracy of the Wells rule to safely exclude PE in older unhospitalized adults suspected of having one.14
METHODS This was an observational cohort study of elderly adults (≥60) suspected of having a PE who were community
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dwelling or residing in nursing homes in the Netherlands (inclusion period July 2007 to April 2013). This clinical suspicion of PE was based on unexplained (deterioration of) dyspnea, pain on inspiration, unexplained cough, or a combination of these symptoms. Individuals were not eligible for inclusion if they were receiving anticoagulant treatment (vitamin K antagonists or oral direct thrombin or factor Xa inhibitors) at presentation or if they declined to provide informed consent. All physicians were provided with written instructions about the logistics of the study and with qualitative point-of-care tests (Clearview Simplify D-dimer assay, Inverness Medical, Princeton, NJ) plus instructions for the performance and interpretation of this test. The ethics review board of the University Medical Center Utrecht, the Netherlands, judged the study to be exempt from review according to national law (08–124/E).
Diagnostic Strategy Under Study The primary aim of this study was to validate the accuracy of the Wells rule combined with qualitative D-dimer testing to exclude PE in elderly unhospitalized adults. Physicians systematically recorded each participant’s medical history and symptoms and signs and the participant’s score on the Wells rule (Table 1).15 The qualitative point-of-care D-dimer test was then administered. Physicians were recommended to refer all individuals with a likely risk of PE according to the Wells rule (>4 points) or an abnormal Ddimer test to secondary care for ultrasonography examinations of the deep veins of the legs, and to refrain from referral in all other individuals (unlikely risk (≤4 points) according to the Wells rule and a normal D-dimer test).
Outcomes The presence of PE was confirmed using a composite reference standard of computed tomography (CT) of the chest, VQ scanning, compression ultrasonography of the leg, 3month follow-up, or any combination of these. All participants were followed up at 3 months to assess the occurrence of any venous thromboembolic event, major and clinically relevant nonmajor bleeding complications (based on the definitions proposed by the International Society on Thrombosis and Hemostasis),16 and—if applicable—cause of death. PE was considered present if there was confirmed PE on CT pulmonary angiography or high-probability VQ scanning of the chest,17 confirmed deep venous thrombosis with ultrasonography of the leg in individuals with clinically suspected PE but without the aforementioned imaging modalities, or death within 3 months that was probably related to PE according to an adjudication committee (see below). An adjudication committee of three experts evaluated all participants who were not referred to a hospital for objective testing despite a high risk of PE (>4) according to the Wells rule or an abnormal D-dimer test and all participants in whom anticoagulant treatment was initiated without objective confirmation of the diagnosis. If—based on all available clinical information—this committee deemed PE to be present, participants were further classified and analyzed accordingly. This committee similarly evaluated deaths and adjudicated them as being probably or not related to PE.
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Table 1. Study Participant Characteristics (N = 294) Characteristic
Value
Patients with confirmed PE, n (%) Demographic characteristics Male, n (%) Age, years, mean SD Residing in nursing home Symptoms, n (%) Unexplained dyspnea Pain on inspiration Chest pain Unexplained cough Acute onset of symptoms Duration of complaints, days, median (interquartile range) Signs Concomitant suspicion of deep venous thrombosis, n (%)a Hemoptysis, n (%)a Tachycardia (>100 beats/minute), n (%)a Heart rate, mean SD Respiratory rate, mean SD Crepitations, n (%) D-dimer abnormal, n (%) Medical history Previous episode of deep venous thrombosisa Previous episode of PEa Chronic obstructive pulmonary disease Heart failure (diagnosed with ultrasonography of the heart) Angina pectoris Myocardial infarction Active malignancya Immobilization or surgery in previous montha Comedication, n (%) Antiplatelet therapy Prophylactic dose of low-molecular-weight heparin
83 (28.2) 99 (33.7) 75.6 10.3 129 (43.9) 190 144 110 77 208 3
(64.6) (49.0) (37.4) (26.2) (70.8) (6)
41 (14.0) 8 (2.7) 82 (27.9) 86.9 18.9 22.1 7.9 103 (35.0) 191 (65.0) 28 (9.5) 37 (12.6) 54 (18.2) 39 (13.3) 36 34 28 88
(12.2) (11.6) (9.5) (29.9)
97 (33.0) 12 (4.1)
PE = pulmonary embolism; SD = standard deviation. a Predictor in the Wells rule.
Analyses Some participants had missing values for one or more Wells rule items, the D-dimer test, or follow-up data ( 4
n = 178
n = 116
D-dimer normal:
D-dimer abnormal:
n = 85
n= 93†
Reference:
Reference:
Reference:
CT n = 25 (29%)
CT or V/Q n = 50 (54%)
CT or V/Q n = 70 (60%)
3 m f-up only n = 61 (71%)
CUS n=3 (2%)
CUS n=3 (2%)
3 m f-up + AC n = 41(44%)
3 m f-up + AC n = 44 (38%)
Total PE events n= 5 (5.9%; 95% CI 2.5 to 13.0%) ‡ Fatal PE-events n= 0 3-month all-cause mortality n= 7 (8.2%) Bleeding n= 0
Total PE-events n= 19
Total PE-events n= 59
(20.4%; 95% CI 13.5 to 29.7%)
(50.9%; 95% CI 41.9 to 59.8%)
Fatal PE-events n=3 (3.2%)
Fatal PE-events n= 8 (6.9%)
3-month all-cause mortality n= 15 (16.1%)
3-month all-cause mortality n= 21 (18.1%)
Major bleeding n=1 (1.1%)
Major bleeding n= 1 (0.9%)
Non-major bleeding n=1 (1.1%)
Non-major bleeding n=2 (1.7%)
Anticoagulant treatment n=26 (28.0%)
Anticoagulant treatment n= 59 (50.9%)
Figure 1. Flow of study participants through the study. *n = 150 patients were entered in the study via the AMUSE2 –study; ‡ one of the missed patients did not undergo reference testing but was adjudicated as PE positive, if this patient were adjudicated as PE negative the failure rate would have been 4.7% (1.8–11.4%); †D-dimer result was invallid or uninterpretable in seven patients. VTE = venous thromboembolism; CT = computed tomography; V/Q = ventilation-perfusion; CUS = compression ultrasonography of the lower extremity, 3 m f-up = 3-month follow-up; AC = adjudication committee; DDimer positive = quantitive D-dimer = 500 lg/L and/or POC DD test positive. POC = point of care.
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Scenario Analyses If physicians had combined a normal D-dimer test with the Wells rule but used a lower threshold (4 points) or an abnormal D-dimer test were not referred for imaging examination. Because physician decisions to withhold imaging examination were related to participant characteristics (referral was notably withheld for the frailest individuals and individuals at the end of life), it was decided not to exclude these individuals to avoid selection of only the fittest elderly adults. Instead, an adjudication committee of experts in the field of venous thromboembolism decided in each of these 85 participants whether it was likely or unlikely that PE was present. This might also have introduced some classification errors of the final diagnosis, but it highly reflects clinical practice. To avoid differential verification bias, predictive values (failure rate) were explicitly focused on —according to recent methodological standards—rather than on estimates of the sensitivity and specificity because differential verification barely affects the former estimates.29,30
Clinical Implications Although there is no consensus on what exact proportion of missed cases is acceptable, many studies have considered a point-estimate of approximately 2% missed cases as acceptable, because these values correspond to the proportion of missed cases given that all suspected participants were referred for the criterion standard (CT pulmonary angiography).8–10,20–25 Based on this safety standard of 2%, the use of a combination of an unlikely risk according to the Wells rule and a normal qualitative D-dimer test to be an unsafe strategy to exclude PE in older unhospitalized adults. In addition, the refitted model does not reach this safety standard of 2%, although the point estimate of 2.9% is much lower than the failure rate of the original Wells model, yet regarding the Wells model (original or refitted) as unsafe would imply that all older adults with suspected PE should be referred for CT; this seems unappealing and unrealistic for this frail population. The fact that referral was withheld in 54% of the nursing home residents who had a high risk according to the Wells rule or an abnormal D-dimer test also illustrates this. The potential risks and burden of additional testing and hospital transfers for older adults (e.g., the risk of contrast-induced nephropathy and functional decline) implicitly played a role in this decision-making.30,31 These considerations and the higher failure rate in older adults than in younger individuals may lead to discussion among elderly care professionals as to whether the (original or refitted) Wells rule might still be considered useful for elderly outpatients with suspected PE. Although medical professionals may consider the failure rate too high, the strategy could contribute to avoidance of burdensome imaging examinations in 29% of elderly outpatients with suspected PE.
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Conclusions and Implications The Wells rule (original or refitted) for PE in combination with a qualitative D-dimer test has a higher failure rate when used in older unhospitalized adults than previous studies in younger individuals have found. The current findings highlight that older unhospitalized adults with suspected PE are a distinct population in whom the use of the well-known and widely used Wells strategy does not guarantee safe exclusion of PE.
ACKNOWLEDGMENTS The authors thank all participants and physicians who participated in the VT-elderly study. They would also like to thank Reinold Siccama, Sharon Berendsen, and the AMUSE-reseachers Wim Lucassen and Petra Erkens for their contribution to the data-collection. Conflict of Interest: None of the authors had financial relationships with any organization that might have an interest in the submitted work in the previous 3 years. None of the authors have relationships or activities that could appear to have influenced the submitted work. The Netherlands Organization for Scientific Research provided financial support (ZonMw project 17088–2502). This organization had no influence on any aspect of this study. Author Contributions: Schouten, Koek: data analysis and interpretation, drafting of manuscript. Schouten, Oudega: data acquisition. Oudega, Moons, van Delden, Geersing: study concept and design, data analysis and interpretation, critical revision of the manuscript. Moons, Geersing, Koek: study supervision. Henrike J. Schouten is guarantor of the work and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in revision and final approval of the manuscript. All authors had full access to the data of the study. Sponsor’s Role: The Netherlands Organization for Scientific Research had no influence on design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
REFERENCES 1. White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:I4–I8. 2. Silverstein MD, Heit JA, Mohr DN et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: A 25-year population-based study. Arch Intern Med 1998;158:585–593. 3. Anderson FA Jr, Wheeler HB, Goldberg RJ et al. 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;151:933–938. 4. Righini M, Le Gal G, Perrier A et al. The challenge of diagnosing pulmonary embolism in elderly patients: Influence of age on commonly used diagnostic tests and strategies. J Am Geriatr Soc 2005;53:1039–1045. 5. Schouten HJ, Geersing GJ, Koek HL et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: Systematic review and meta-analysis. BMJ 2013;346:f2492.
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6. Gozalo P, Teno JM, Mitchell SL et al. End-of-life transitions among nursing home residents with cognitive issues. N Engl J Med 2011;365:1212– 1221. 7. Mitchell AM, Jones AE, Tumlin JA et al. Prospective study of the incidence of contrast-induced nephropathy among patients evaluated for pulmonary embolism by contrast-enhanced computed tomography. Acad Emerg Med 2012;19:618–625. 8. Wells PS, Anderson DR, Rodger M et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med 2001;135:98–107. 9. Geersing GJ, Erkens PM, Lucassen WA et al. Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: Prospective cohort study. BMJ 2012;345:e6564. 10. Lucassen W, Geersing GJ, Erkens PM et al. Clinical decision rules for excluding pulmonary embolism: A meta-analysis. Ann Intern Med 2011;155:448–460. 11. Moons KG, Altman DG, Vergouwe Y et al. Prognosis and prognostic research: Application and impact of prognostic models in clinical practice. BMJ 2009;338:b606. 12. Reilly BM, Evans AT. Translating clinical research into clinical practice: Impact of using prediction rules to make decisions. Ann Intern Med 2006;144:201–209. 13. Schouten HJ, Koek HL, Moons KG et al. Need for tailored strategies to diagnose venous thrombo-embolism in older primary care patients. Extension of a keynote presentation at the 2012 Wonca Europe conference. Eur J Gen Pract 2013;19:123–127. 14. Moons KG, Kengne AP, Grobbee DE et al. Risk prediction models: II. External validation, model updating, and impact assessment. Heart 2012;98:691–698. 15. Wells PS, Anderson DR, Rodger M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: Increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416–420. 16. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–694. 17. Sostman HD, Miniati M, Gottschalk A et al. Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med 2008;49:1741–1748. 18. Newcombe RG. Estimating the difference between differences: Measurement of additive scale interaction for proportions. Stat Med 2001;20:2885–2893. 19. Steyerberg EW, Borsboom GJ, van Houwelingen HC et al. Validation and updating of predictive logistic regression models: A study on sample size and shrinkage. Stat Med 2004;23:2567–2586. 20. van Belle A, Buller HR, Huisman MV et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295:172–179. 21. Goekoop RJ, Steeghs N, Niessen RW et al. Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells’ simplified decision rule. Thromb Haemost 2007;97:146–150.
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22. Steeghs N, Goekoop RJ, Niessen RW et al. C-reactive protein and D-dimer with clinical probability score in the exclusion of pulmonary embolism. Br J Haematol 2005;130:614–619. 23. Douma RA, Mos IC, Erkens PM et al. Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: A prospective cohort study. Ann Intern Med 2011;154:709–718. 24. Kearon C, Ginsberg JS, Douketis J et al. An evaluation of D-dimer in the diagnosis of pulmonary embolism: A randomized trial. Ann Intern Med 2006;144:812–821. 25. Klok FA, Kruisman E, Spaan J et al. Comparison of the revised Geneva score with the Wells rule for assessing clinical probability of pulmonary embolism. J Thromb Haemost 2008;6:40–44. 26. Spyropoulos AC, Merli G. Management of venous thromboembolism in the elderly. Drugs Aging 2006;23:651–671. 27. Geersing GJ, Janssen KJ, Oudega R et al. Excluding venous thromboembolism using point of care D-dimer tests in outpatients: A diagnostic metaanalysis. BMJ 2009;339:b2990. 28. Buller HR, Ten Cate-Hoek AJ, Hoes AW et al. Safely ruling out deep venous thrombosis in primary care. Ann Intern Med 2009;150:229–235. 29. Naaktgeboren CA, de Groot JA, van Smeden M et al. Evaluating diagnostic accuracy in the face of multiple reference standards. Ann Intern Med 2013;159:195–202. 30. Gill TM, Gahbauer EA, Han L et al. The relationship between intervening hospitalizations and transitions between frailty states. J Gerontol A Biol Sci Med Sci 2011;66A:1238–1243. 31. Fried TR, Mor V. Frailty and hospitalization of long-term stay nursing home residents. J Am Geriatr Soc 1997;45:265–269.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Clinical decision rule under study; the Wells rule. Table S2. Refitted diagnostic strategy for the elderly to refute or diagnose PE. Figure S1. Diagnostic accuracy of the refitted Wells rule. Please note: Wiley-Blackwell is not responsible for the content, accuracy, errors, or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.
Copyright of Journal of the American Geriatrics Society is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
OBJECTIVES: To determine whether the Wells clinical prediction rule for pulmonary embolism (PE), which produces a point score based on clinical features and the likelihood of diagnoses other than PE, combined with normal D-dimer testing can be used to exclude PE in older unhospitalized adults. DESIGN: Prospective cohort study. SETTING: Primary care and nursing homes. PARTICIPANTS: Older adults (≥60) clinically suspected of having a PE (N = 294, mean age 76, 44% residing in a nursing home). MEASUREMENTS: The presence of PE was confirmed using a composite reference standard including computed tomography and 3-month follow-up. The proportion of individuals with an unlikely risk of PE was calculated according to the Wells rule (≤4 points) plus a normal qualitative point-of-care D-dimer test (efficiency) and the presence of symptomatic PE during 3 months of follow-up within these patients (failure rate). RESULTS: Pulmonary embolism occurred in 83 participants (28%). Eighty-five participants had an unlikely risk according to the Wells rule and a normal D-dimer test (efficiency 29%), five of whom experienced a nonfatal PE during 3 months of follow-up (failure rate = 5.9%, 95% confidence interval (CI) = 2.5–13%). According to a refitted diagnostic strategy for older adults, 69 had a low risk of PE (24%), two of whom had PE (failure rate = 2.9%, 95% CI = 0.8–10%). CONCLUSION: The use of the well-known and widely used Wells rule (original or refitted) does not guarantee safe exclusion of PE in older unhospitalized adults with suspected PE. This may lead to discussion among professionals as to whether the original or revised Wells rule is
From the *Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, and †Department of Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands. Address correspondence to Henrike J. Schouten, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Str 6.131, PO Box 85500, Utrecht, 3508GA, the Netherlands. E-mail: [email protected] DOI: 10.1111/jgs.13080
JAGS 62:2136–2141, 2014 © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society
useful for elderly outpatients. J Am Geriatr Soc 62:2136– 2141, 2014.
Key words: pulmonary embolism; elderly; diagnosis; venous thromboembolism; nursing home; D-dimer; geriatric; Wells; clinical decision rule
G
iven the exponential rise of the incidence of venous thromboembolism with increasing age, the majority of (potentially fatal) pulmonary emboli (PEs) occur in older adults.1–3 Although accurately and timely diagnosis of PE can be lifesaving, it is notoriously difficult in elderly adults, in whom clinical symptoms and signs of PE can be subtle or obscured by other cardiac or pulmonary comorbidities.4 Consequently, physicians need to refer many older adults suspected of having a PE to confirm one case. (One in five individuals with suspected PE has confirmed PE.5) This can be burdensome, given that this population is particularly vulnerable to distress resulting from transitions for hospital care.6,7 Diagnostic decision rules—such as the Wells rule combined with D-dimer testing—have been developed to distinguish a subgroup of participants in whom PE can be excluded without referral for imaging examination.8 This exclusion strategy has been extensively validated in primary and hospital care, mainly in younger adults,9,10 but the accuracy of the existing clinical decision rules to exclude PE has never been tested in elderly populations. This is important because a change in setting (e.g., from hospital to nursing home care) results in a different case mix, which may affect the diagnostic accuracy and thus generalizability of decision rules.11–13 Therefore, this prospective study was conducted to assess the accuracy of the Wells rule to safely exclude PE in older unhospitalized adults suspected of having one.14
METHODS This was an observational cohort study of elderly adults (≥60) suspected of having a PE who were community
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dwelling or residing in nursing homes in the Netherlands (inclusion period July 2007 to April 2013). This clinical suspicion of PE was based on unexplained (deterioration of) dyspnea, pain on inspiration, unexplained cough, or a combination of these symptoms. Individuals were not eligible for inclusion if they were receiving anticoagulant treatment (vitamin K antagonists or oral direct thrombin or factor Xa inhibitors) at presentation or if they declined to provide informed consent. All physicians were provided with written instructions about the logistics of the study and with qualitative point-of-care tests (Clearview Simplify D-dimer assay, Inverness Medical, Princeton, NJ) plus instructions for the performance and interpretation of this test. The ethics review board of the University Medical Center Utrecht, the Netherlands, judged the study to be exempt from review according to national law (08–124/E).
Diagnostic Strategy Under Study The primary aim of this study was to validate the accuracy of the Wells rule combined with qualitative D-dimer testing to exclude PE in elderly unhospitalized adults. Physicians systematically recorded each participant’s medical history and symptoms and signs and the participant’s score on the Wells rule (Table 1).15 The qualitative point-of-care D-dimer test was then administered. Physicians were recommended to refer all individuals with a likely risk of PE according to the Wells rule (>4 points) or an abnormal Ddimer test to secondary care for ultrasonography examinations of the deep veins of the legs, and to refrain from referral in all other individuals (unlikely risk (≤4 points) according to the Wells rule and a normal D-dimer test).
Outcomes The presence of PE was confirmed using a composite reference standard of computed tomography (CT) of the chest, VQ scanning, compression ultrasonography of the leg, 3month follow-up, or any combination of these. All participants were followed up at 3 months to assess the occurrence of any venous thromboembolic event, major and clinically relevant nonmajor bleeding complications (based on the definitions proposed by the International Society on Thrombosis and Hemostasis),16 and—if applicable—cause of death. PE was considered present if there was confirmed PE on CT pulmonary angiography or high-probability VQ scanning of the chest,17 confirmed deep venous thrombosis with ultrasonography of the leg in individuals with clinically suspected PE but without the aforementioned imaging modalities, or death within 3 months that was probably related to PE according to an adjudication committee (see below). An adjudication committee of three experts evaluated all participants who were not referred to a hospital for objective testing despite a high risk of PE (>4) according to the Wells rule or an abnormal D-dimer test and all participants in whom anticoagulant treatment was initiated without objective confirmation of the diagnosis. If—based on all available clinical information—this committee deemed PE to be present, participants were further classified and analyzed accordingly. This committee similarly evaluated deaths and adjudicated them as being probably or not related to PE.
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Table 1. Study Participant Characteristics (N = 294) Characteristic
Value
Patients with confirmed PE, n (%) Demographic characteristics Male, n (%) Age, years, mean SD Residing in nursing home Symptoms, n (%) Unexplained dyspnea Pain on inspiration Chest pain Unexplained cough Acute onset of symptoms Duration of complaints, days, median (interquartile range) Signs Concomitant suspicion of deep venous thrombosis, n (%)a Hemoptysis, n (%)a Tachycardia (>100 beats/minute), n (%)a Heart rate, mean SD Respiratory rate, mean SD Crepitations, n (%) D-dimer abnormal, n (%) Medical history Previous episode of deep venous thrombosisa Previous episode of PEa Chronic obstructive pulmonary disease Heart failure (diagnosed with ultrasonography of the heart) Angina pectoris Myocardial infarction Active malignancya Immobilization or surgery in previous montha Comedication, n (%) Antiplatelet therapy Prophylactic dose of low-molecular-weight heparin
83 (28.2) 99 (33.7) 75.6 10.3 129 (43.9) 190 144 110 77 208 3
(64.6) (49.0) (37.4) (26.2) (70.8) (6)
41 (14.0) 8 (2.7) 82 (27.9) 86.9 18.9 22.1 7.9 103 (35.0) 191 (65.0) 28 (9.5) 37 (12.6) 54 (18.2) 39 (13.3) 36 34 28 88
(12.2) (11.6) (9.5) (29.9)
97 (33.0) 12 (4.1)
PE = pulmonary embolism; SD = standard deviation. a Predictor in the Wells rule.
Analyses Some participants had missing values for one or more Wells rule items, the D-dimer test, or follow-up data ( 4
n = 178
n = 116
D-dimer normal:
D-dimer abnormal:
n = 85
n= 93†
Reference:
Reference:
Reference:
CT n = 25 (29%)
CT or V/Q n = 50 (54%)
CT or V/Q n = 70 (60%)
3 m f-up only n = 61 (71%)
CUS n=3 (2%)
CUS n=3 (2%)
3 m f-up + AC n = 41(44%)
3 m f-up + AC n = 44 (38%)
Total PE events n= 5 (5.9%; 95% CI 2.5 to 13.0%) ‡ Fatal PE-events n= 0 3-month all-cause mortality n= 7 (8.2%) Bleeding n= 0
Total PE-events n= 19
Total PE-events n= 59
(20.4%; 95% CI 13.5 to 29.7%)
(50.9%; 95% CI 41.9 to 59.8%)
Fatal PE-events n=3 (3.2%)
Fatal PE-events n= 8 (6.9%)
3-month all-cause mortality n= 15 (16.1%)
3-month all-cause mortality n= 21 (18.1%)
Major bleeding n=1 (1.1%)
Major bleeding n= 1 (0.9%)
Non-major bleeding n=1 (1.1%)
Non-major bleeding n=2 (1.7%)
Anticoagulant treatment n=26 (28.0%)
Anticoagulant treatment n= 59 (50.9%)
Figure 1. Flow of study participants through the study. *n = 150 patients were entered in the study via the AMUSE2 –study; ‡ one of the missed patients did not undergo reference testing but was adjudicated as PE positive, if this patient were adjudicated as PE negative the failure rate would have been 4.7% (1.8–11.4%); †D-dimer result was invallid or uninterpretable in seven patients. VTE = venous thromboembolism; CT = computed tomography; V/Q = ventilation-perfusion; CUS = compression ultrasonography of the lower extremity, 3 m f-up = 3-month follow-up; AC = adjudication committee; DDimer positive = quantitive D-dimer = 500 lg/L and/or POC DD test positive. POC = point of care.
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Scenario Analyses If physicians had combined a normal D-dimer test with the Wells rule but used a lower threshold (4 points) or an abnormal D-dimer test were not referred for imaging examination. Because physician decisions to withhold imaging examination were related to participant characteristics (referral was notably withheld for the frailest individuals and individuals at the end of life), it was decided not to exclude these individuals to avoid selection of only the fittest elderly adults. Instead, an adjudication committee of experts in the field of venous thromboembolism decided in each of these 85 participants whether it was likely or unlikely that PE was present. This might also have introduced some classification errors of the final diagnosis, but it highly reflects clinical practice. To avoid differential verification bias, predictive values (failure rate) were explicitly focused on —according to recent methodological standards—rather than on estimates of the sensitivity and specificity because differential verification barely affects the former estimates.29,30
Clinical Implications Although there is no consensus on what exact proportion of missed cases is acceptable, many studies have considered a point-estimate of approximately 2% missed cases as acceptable, because these values correspond to the proportion of missed cases given that all suspected participants were referred for the criterion standard (CT pulmonary angiography).8–10,20–25 Based on this safety standard of 2%, the use of a combination of an unlikely risk according to the Wells rule and a normal qualitative D-dimer test to be an unsafe strategy to exclude PE in older unhospitalized adults. In addition, the refitted model does not reach this safety standard of 2%, although the point estimate of 2.9% is much lower than the failure rate of the original Wells model, yet regarding the Wells model (original or refitted) as unsafe would imply that all older adults with suspected PE should be referred for CT; this seems unappealing and unrealistic for this frail population. The fact that referral was withheld in 54% of the nursing home residents who had a high risk according to the Wells rule or an abnormal D-dimer test also illustrates this. The potential risks and burden of additional testing and hospital transfers for older adults (e.g., the risk of contrast-induced nephropathy and functional decline) implicitly played a role in this decision-making.30,31 These considerations and the higher failure rate in older adults than in younger individuals may lead to discussion among elderly care professionals as to whether the (original or refitted) Wells rule might still be considered useful for elderly outpatients with suspected PE. Although medical professionals may consider the failure rate too high, the strategy could contribute to avoidance of burdensome imaging examinations in 29% of elderly outpatients with suspected PE.
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Conclusions and Implications The Wells rule (original or refitted) for PE in combination with a qualitative D-dimer test has a higher failure rate when used in older unhospitalized adults than previous studies in younger individuals have found. The current findings highlight that older unhospitalized adults with suspected PE are a distinct population in whom the use of the well-known and widely used Wells strategy does not guarantee safe exclusion of PE.
ACKNOWLEDGMENTS The authors thank all participants and physicians who participated in the VT-elderly study. They would also like to thank Reinold Siccama, Sharon Berendsen, and the AMUSE-reseachers Wim Lucassen and Petra Erkens for their contribution to the data-collection. Conflict of Interest: None of the authors had financial relationships with any organization that might have an interest in the submitted work in the previous 3 years. None of the authors have relationships or activities that could appear to have influenced the submitted work. The Netherlands Organization for Scientific Research provided financial support (ZonMw project 17088–2502). This organization had no influence on any aspect of this study. Author Contributions: Schouten, Koek: data analysis and interpretation, drafting of manuscript. Schouten, Oudega: data acquisition. Oudega, Moons, van Delden, Geersing: study concept and design, data analysis and interpretation, critical revision of the manuscript. Moons, Geersing, Koek: study supervision. Henrike J. Schouten is guarantor of the work and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in revision and final approval of the manuscript. All authors had full access to the data of the study. Sponsor’s Role: The Netherlands Organization for Scientific Research had no influence on design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Clinical decision rule under study; the Wells rule. Table S2. Refitted diagnostic strategy for the elderly to refute or diagnose PE. Figure S1. Diagnostic accuracy of the refitted Wells rule. Please note: Wiley-Blackwell is not responsible for the content, accuracy, errors, or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.
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