Diagnosis Systematic review
A low Wells score and a negative D-dimer was not safe in patients with cancer for ruling out DVT 10.1136/eb-2014-110014
Alfonso Tafur Department of Medicine, Internal Medicine-Cardiovascular, Oklahoma University Health and Science Center, Oklahoma City, Oklahoma, USA Correspondence to: Dr Alfonso Tafur, Department of Medicine, Internal Medicine-Cardiovascular, Oklahoma University Health and Science Center, Oklahoma City, OK 73013, USA; [email protected]
Context In combination with a D-dimer serum test, the Wells rule has long been used and recommended to help clinicians discern the likelihood of lower extremity deep vein thrombosis (DVT).1 The safety and efficacy of these tools have been challenged in their applications to populations with distinct incidences of DVT.2 Specifically, patients with a prior DVT and those with malignancy have a high rate of venous thromboembolism (VTE) which may foreseeably decrease the negative predictive value of prediction rules. These specific populations have not been well represented in individual studies.
Methods For the current study, Geersing et al3 performed a patient-level meta-analysis by combining data extracted from 13 studies published after 2006. The inclusion criteria were restricted to those studies with data on all the predictors of the Wells rule, and D-dimer before the reference test. The accepted reference tests for proximal DVT were compression ultrasound or venography, but if these were absent an uneventful follow-up for 3 months was an acceptable reference for a negative study. When generating the new database, missing values were imputed within individual datasets (up to 1% for DVT, 2% for malignancy and 5% for the ‘alternative diagnosis’ question on the Wells rule). D-dimer values were not imputed. There were D-dimer data for 7625 patients. The authors calculated the failure rate and the efficiency of a combined low Wells score (≤1) and a negative D-dimer. The efficiency represents the proportion of patients in which a DVT may be excluded. The results were stratified by predefined subgroups including: case setting ( primary vs secondary or hospital), malignancy, gender and prior DVT.
Findings There were 10 002 patients included of which 19% had a proximal DVT. Most of the studies (10 of 13) were in a hospital setting and seven excluded patients with a history of prior DVT. There was a high rate of failure when the Wells score was calculated as a single tool to rule out DVT, even with a strong score of −2 (failure rate 2–5.9%). The combination of a low Wells score and negative D-dimer had a lower failure rate (1.2%, 95% CI 0.7% to 1.8%). The combination rule was safe in primary care, hospital setting and in both genders, and had an overall efficiency of 28.9 (20.3 to 39.5). The failure rate in patients with cancer and prior DVTs were 2.2% (0.5% to 8.6%) and 2.5% (1.2 to 5.4), respectively. Moreover, the efficiency of the combined rule was especially low among patients with active cancer (9.1; 5.5 to 14.7). Adding a point to the Wells score for the patients with a history of DVT (updated Wells score) resulted
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in an improvement in the overall failure rate to 1% (0.6% to 1.6%) and efficiency to 27.2% (19.2% to 37%). The authors concluded that the use of the combined rule of a low Wells score and a negative D-dimer was not safe in patients with cancer for ruling out DVT; however, the updated Wells score was safe for clinical use for patients with a prior history of DVT.
Comment Clinicians may continue to use the combination of a Wells score and D-dimer to safely rule out DVT in most settings, reflecting the current guideline recommendations1; however, special attention is needed for patients with cancer and those with prior DVT. In these groups the failure rate of the combined Wells score and D-dimer was unsafe, but there was limited inclusion of patients with malignancy (n=834) or prior DVT (n=941) in this meta-analysis. VTE is one of the leading causes of death among patients with cancer and affects up to 20% of this population.4 In addition, many patients with cancer present with atypical symptoms of VTE, yet the prognosis is the same for incidental or suspected VTE.5 Thus, clinicians must be cautious when subtracting two points from a Wells score for ‘alternative diagnosis as likely as or more likely than deep vein thrombosis’,3 as doing so translates into inefficient Wells scores that this meta-analysis elegantly quantified. The ‘alternative diagnosis’ variable was imputed in 5% of the database, but the direct effect to the subgroup of patients with cancer was expected to be balanced. The diagnosis of recurrent DVT in the same leg is a major clinical dilemma; residual vein thrombosis may be mistaken as a recurrent event for which long-term anticoagulation might be recommended. The inter observer agreement for vein diameter on compression ultrasound is low,6 yet this is one of the main tools used to diagnose ipsilateral recurrence of DVT. Most of the studies included in this meta-analysis used ultrasound as the main reference standard and there were no details provided on the frequency of ipsilateral recurrences in these studies. This patient level meta-analysis sheds light on at least two areas that require further diagnostic improvement: (1) exploring clinical prediction scores specific to patients with cancer and (2) studying the accuracy of alternative imaging techniques to improve the characterisation of a residual clot. For now, the inefficiency of the combined rule for patients with prior DVT may be circumvented by adopting the updated Wells score. Competing interests None.
References 1. Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e351S–418S. 2. Schutgens RE, Beckers MM, Haas FJ, et al. The predictive value of D-dimer measurement for cancer in patients with deep vein thrombosis. Haematologica 2005;90:214–19. 3. Geersing GJ, Zuithoff NP, Kearon C, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ 2014;348:g1340. 4. Khorana AA, Francis CW, Culakova E, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007;110:2339–46. 5. den Exter PL, Hooijer J, Dekkers OM, et al. Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol 2011;29:2405–9. 6. Linkins LA, Stretton R, Probyn L, et al. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res 2006;117:241–7.
A low Wells score and a negative D-dimer was not safe in patients with cancer for ruling out DVT 10.1136/eb-2014-110014
Alfonso Tafur Department of Medicine, Internal Medicine-Cardiovascular, Oklahoma University Health and Science Center, Oklahoma City, Oklahoma, USA Correspondence to: Dr Alfonso Tafur, Department of Medicine, Internal Medicine-Cardiovascular, Oklahoma University Health and Science Center, Oklahoma City, OK 73013, USA; [email protected]
Context In combination with a D-dimer serum test, the Wells rule has long been used and recommended to help clinicians discern the likelihood of lower extremity deep vein thrombosis (DVT).1 The safety and efficacy of these tools have been challenged in their applications to populations with distinct incidences of DVT.2 Specifically, patients with a prior DVT and those with malignancy have a high rate of venous thromboembolism (VTE) which may foreseeably decrease the negative predictive value of prediction rules. These specific populations have not been well represented in individual studies.
Methods For the current study, Geersing et al3 performed a patient-level meta-analysis by combining data extracted from 13 studies published after 2006. The inclusion criteria were restricted to those studies with data on all the predictors of the Wells rule, and D-dimer before the reference test. The accepted reference tests for proximal DVT were compression ultrasound or venography, but if these were absent an uneventful follow-up for 3 months was an acceptable reference for a negative study. When generating the new database, missing values were imputed within individual datasets (up to 1% for DVT, 2% for malignancy and 5% for the ‘alternative diagnosis’ question on the Wells rule). D-dimer values were not imputed. There were D-dimer data for 7625 patients. The authors calculated the failure rate and the efficiency of a combined low Wells score (≤1) and a negative D-dimer. The efficiency represents the proportion of patients in which a DVT may be excluded. The results were stratified by predefined subgroups including: case setting ( primary vs secondary or hospital), malignancy, gender and prior DVT.
Findings There were 10 002 patients included of which 19% had a proximal DVT. Most of the studies (10 of 13) were in a hospital setting and seven excluded patients with a history of prior DVT. There was a high rate of failure when the Wells score was calculated as a single tool to rule out DVT, even with a strong score of −2 (failure rate 2–5.9%). The combination of a low Wells score and negative D-dimer had a lower failure rate (1.2%, 95% CI 0.7% to 1.8%). The combination rule was safe in primary care, hospital setting and in both genders, and had an overall efficiency of 28.9 (20.3 to 39.5). The failure rate in patients with cancer and prior DVTs were 2.2% (0.5% to 8.6%) and 2.5% (1.2 to 5.4), respectively. Moreover, the efficiency of the combined rule was especially low among patients with active cancer (9.1; 5.5 to 14.7). Adding a point to the Wells score for the patients with a history of DVT (updated Wells score) resulted
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in an improvement in the overall failure rate to 1% (0.6% to 1.6%) and efficiency to 27.2% (19.2% to 37%). The authors concluded that the use of the combined rule of a low Wells score and a negative D-dimer was not safe in patients with cancer for ruling out DVT; however, the updated Wells score was safe for clinical use for patients with a prior history of DVT.
Comment Clinicians may continue to use the combination of a Wells score and D-dimer to safely rule out DVT in most settings, reflecting the current guideline recommendations1; however, special attention is needed for patients with cancer and those with prior DVT. In these groups the failure rate of the combined Wells score and D-dimer was unsafe, but there was limited inclusion of patients with malignancy (n=834) or prior DVT (n=941) in this meta-analysis. VTE is one of the leading causes of death among patients with cancer and affects up to 20% of this population.4 In addition, many patients with cancer present with atypical symptoms of VTE, yet the prognosis is the same for incidental or suspected VTE.5 Thus, clinicians must be cautious when subtracting two points from a Wells score for ‘alternative diagnosis as likely as or more likely than deep vein thrombosis’,3 as doing so translates into inefficient Wells scores that this meta-analysis elegantly quantified. The ‘alternative diagnosis’ variable was imputed in 5% of the database, but the direct effect to the subgroup of patients with cancer was expected to be balanced. The diagnosis of recurrent DVT in the same leg is a major clinical dilemma; residual vein thrombosis may be mistaken as a recurrent event for which long-term anticoagulation might be recommended. The inter observer agreement for vein diameter on compression ultrasound is low,6 yet this is one of the main tools used to diagnose ipsilateral recurrence of DVT. Most of the studies included in this meta-analysis used ultrasound as the main reference standard and there were no details provided on the frequency of ipsilateral recurrences in these studies. This patient level meta-analysis sheds light on at least two areas that require further diagnostic improvement: (1) exploring clinical prediction scores specific to patients with cancer and (2) studying the accuracy of alternative imaging techniques to improve the characterisation of a residual clot. For now, the inefficiency of the combined rule for patients with prior DVT may be circumvented by adopting the updated Wells score. Competing interests None.
References 1. Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e351S–418S. 2. Schutgens RE, Beckers MM, Haas FJ, et al. The predictive value of D-dimer measurement for cancer in patients with deep vein thrombosis. Haematologica 2005;90:214–19. 3. Geersing GJ, Zuithoff NP, Kearon C, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ 2014;348:g1340. 4. Khorana AA, Francis CW, Culakova E, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007;110:2339–46. 5. den Exter PL, Hooijer J, Dekkers OM, et al. Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. J Clin Oncol 2011;29:2405–9. 6. Linkins LA, Stretton R, Probyn L, et al. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res 2006;117:241–7.
