NEWS & VIEWS The Wells rule is not accurate in hospitalized patients Walter Ageno Refers to Silveira, P. C. et al. Performance of Wells score for deep vein thrombosis in the inpatient setting. JAMA Intern. Med. http:// dx.doi.org/10.1001/jamainternmed.2015.1687
The Wells rule is the most widely used pretest clinical probability score for patients with suspected deep-vein thrombosis. However, the rule was developed and validated in the outpatient setting, and its accuracy in hospitalized patients has not been investigated previously. A new study indicates that this rule should not be used in the inpatient setting. Signs and symptoms of deep-vein thrombosis (DVT) of the lower limbs—including leg swelling, redness, and pain—are nonspecific. For this reason, objective testing is required to accurately diagnose this potentially lifethreatening disease, and compression ultrasonography, with a 94% sensitivity and a 98% specificity for DVT affecting the femoral and popliteal veins,1 is widely used for this purpose. However, of all patients referred for diagnostic testing services owing to suspected DVT, only 10–20% actually have the disease; in the remaining patients, the most common reasons for leg complaints include muscle tear, infections, arthritis, chronic venous insufficiency, muscle haematoma, or sciatic nerve pain.2 To avoid referral for objective testing in low-risk patients, and to increase the accuracy of the diagnostic imaging test according to Bayes’ theorem,3 various clinical decision rules have been developed to provide a pretest stratification of risk of DVT. These decision rules combine signs, symptoms, and the presence of risk factors to yield a score to be used to estimate the probability of DVT being present. The most widely used pretest probability assessment tool was developed by Wells and colleagues ~20 years ago.4,5 The rule was tested and validated in the outpatient setting, but is sometimes also used in hospitalized patients. However, in a new cohort study, Silveira et al. assessed the performance of the Wells rule in the inpatient setting, and found that the use of this risk stratification is not safe to rule out DVT or to influence management decisions.6 Wells and colleagues initially identified nine clinical features that were significantly
associated with DVT:5 eight positive variables that included three risk factors for DVT (active cancer; paralysis, paresis, or recent plaster immobilization of the lower extremities; and recently bedridden for ≥3 days, or major surgery within the previous 12 weeks requiring general or regional anaesthesia) and five signs suggestive of DVT (localized tenderness along the distribution of the deep venous system, entire leg swollen, calf swelling ≥3 cm larger than that on the asymptomatic leg, pitting oedema confined to the symptomatic leg, and collateral superficial veins), and one negative variable (alternative diagnosis at least as likely as DVT). The resulting score was tested in the out patient setting in a pivotal study, in which a reduction in the rates of false-negative and false-positive ultrasonography studies was shown.5 An additional variable—the presence of previously documented DVT—was subsequently added to the clinical model.7 This modified model, in combination with the measurement of d‑dimer, was shown to safely reduce the need for ultrasound imaging and to allow a rapid exclusion of DVT in a substantial proportion of patients.7 The results of a number of management studies subsequently confirmed the accuracy of the Wells rule and the safety of withholding anticoagulant therapy in patients with suspected venous thromboembolism on the basis of pretest probability assessment and d‑dimer measurement.8 Clinical guidelines recommend that pretest probability assessment should guide the choice of diagnostic tests in patients with a suspected DVT of the lower limbs, and that no further
NATURE REVIEWS | CARDIOLOGY
testing should be considered in patients with a low pretest probability and a negative d‑dimer measurement.9 However, concerns existed about the validity of pretest probability assessment in particular subgroups of patients. For example, the accuracy of the Wells rule might be reduced in patient groups at high risk of DVT, such as in patients with cancer or in hospitalized patients, because the actual prevalence of DVT is expected to be higher in these groups. Another possible concern related to the accuracy of the assessment when performed by different specialists, such as primary care physicians and hospitalbased emergency doctors. To address these important issues, Geersing et al. carried out a meta-analysis of individual patient data from 13 studies and published their findings in 2014.10 The investigators confirmed that, in general, the probability of DVT is extremely low in patients determined to have low pretest probability using the Wells rule and with a negative d‑dimer measurement, and that this finding applies to patients presenting in primary as well as in hospital care.10 However, they also showed that this combination of tests was inaccurate and, therefore, unsafe in patients with cancer; in this population, the incidence of DVT was 2% in the ‘low-risk’ group, with the upper limit of the 95% confidence interval exceeding 8%.10 As explained by the study
BSIP SA/Alamy
VENOUS THROMBOEMBOLISM
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS investigators, the pretest probability of DVT in patients with cancer is higher than in patients without cancer, reducing the negative predictive value of pretest probability assessment.10 None of the studies selected for this meta-analysis included inpatients and, therefore, no conclusions on the safety of this approach in this setting could be drawn. In Silveira et al.’s more-recent cohort study to assess the performance of the Wells rule in the inpatient setting, the incidence of DVT in the group of patients determined as having low pretest probability was as high as 6%, with the upper limit of the 95% confidence interval exceeding 11%.6 The area under the curve for discrimination accuracy of the Wells rule in this study was 0.60.6 Therefore, the investigators concluded that the rule “performed only slightly better than chance for discrimination of risk for DVT in hospitalized patients”.6 The findings indicate that the use of the Wells rule in hospitalized patients to exclude the possibility of DVT is not safe and should not influence management decisions. The results of this study confirm that predictive scores should be used only in the populations in which they have been validated. The average risk profile of out patients—in whom the Wells rule was developed and validated—is different from that of an inpatient population.4,5,7 In the first validation study by Wells and colleagues, the proportion of patients with cancer was 13%, and the proportion of patients with recent surgery, paralysis, or recent immobilization (including immobilization with plaster or recently bedridden) was 19%.5 Subsequent studies carried out in the outpatient setting reported very similar figures. Conversely, in the study of inpatients by Silveira and colleagues, the proportion of patients with cancer was nearly threefold higher (37%),
and the proportion of patients with surgery, paralysis, or recent immobilization was more than fourfold higher (89%).6 Another important difference was in the rate of alternative diagnoses that were at least as likely as DVT, which was 48% in studies performed in outpatients10 and 22% in this cohort study of inpatients.6 Consequently, the proportion of patients categorized as being at ‘low risk’ was 55% in the study by Wells et al. and only 11% in the study by Silveira and colleagues, and the proportion of patients categorized as being at ‘high risk’ was 12% and 44%, respectively.5,6 Moreover, 93% of inpatients had elevated d‑dimer levels.6 Surprisingly, despite the higher risk profile of the population enrolled in the study by Silveira and colleagues, the incidence of objectively confirmed DVT was as low as 12%, possibly because of the widespread use of pharmacological prophylaxis in this setting. The use of thromboprophylaxis might also explain the narrow incremental difference in the incidence of DVT across risk groups in the study by Silveira and colleagues—from 6% in the ‘low-risk’ group to 16% in the ‘high-risk’ group.6 In the study by Wells and colleagues, in which we can assume that only a minority of patients was receiving anticoagulation for the prevention of DVT (data not reported), the incremental difference in the incidence of DVT was much broader and ranged from 3% to 75%.5 To conclude, the use of the Wells rule to exclude the possibility of DVT in hospitalized patients is not safe. Until a specifically designed score based on clinical predictors derived from an inpatient population is developed and validated, doctors should refrain from using clinical prediction rules and d‑dimer measurement in hospitalized patients with suspected DVT to drive their diagnostic decisions.
2 | ADVANCE ONLINE PUBLICATION
Department of Clinical and Experimental Medicine, University of Insubria, Viale Borri 57, Varese 21100, Italy. [email protected] doi:10.1038/nrcadio.2015.106 Published online 7 July 2015 Competing interests The author declares no competing interests. 1.
Goodacre, S., Sampson, F., Thomas, S., van Beek, E. & Sutton, A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med. Imaging 5, 6 (2005). 2. Camporese, G. et al. Outcome of patients with suspected lower limb symptomatic deep vein thrombosis and a normal ultrasoundbased initial diagnostic workup: a prospective study. J. Thromb. Haemost. 10, 2605–2606 (2012). 3. Bayes, T. An essay towards solving a problem in the doctrine of chances. Philos. Trans. R. Soc. London 53, 370–418 (1763). 4. Wells, P. S. et al. Accuracy of clinical assessment of deep vein thrombosis. Lancet 345, 1326–1329 (1995). 5. Wells P. S. et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 350, 1795–1798 (1997). 6. Silveira, P. C. et al. Performance of Wells score for deep vein thrombosis in the inpatient setting. JAMA Intern. Med. http://dx.doi.org/ 10.1001/jamainternmed.2015.1687. 7. Wells, P. S. et al. Evaluation of D‑dimer in the diagnosis of suspected deep-vein thrombosis. N. Engl. J. Med. 349, 1227–1235 (2003). 8. Ten Cate-Hoek, A. J. & Prins, M. H. Management studies using a combination of D‑dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J. Thromb. Haemost. 3, 2465–2470 (2005). 9. Bates, S. M. et al. Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141 (Suppl.), e351S–e418S (2012). 10. Geersing, G. J. et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ 348, g1340 (2014).
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
The Wells rule is the most widely used pretest clinical probability score for patients with suspected deep-vein thrombosis. However, the rule was developed and validated in the outpatient setting, and its accuracy in hospitalized patients has not been investigated previously. A new study indicates that this rule should not be used in the inpatient setting. Signs and symptoms of deep-vein thrombosis (DVT) of the lower limbs—including leg swelling, redness, and pain—are nonspecific. For this reason, objective testing is required to accurately diagnose this potentially lifethreatening disease, and compression ultrasonography, with a 94% sensitivity and a 98% specificity for DVT affecting the femoral and popliteal veins,1 is widely used for this purpose. However, of all patients referred for diagnostic testing services owing to suspected DVT, only 10–20% actually have the disease; in the remaining patients, the most common reasons for leg complaints include muscle tear, infections, arthritis, chronic venous insufficiency, muscle haematoma, or sciatic nerve pain.2 To avoid referral for objective testing in low-risk patients, and to increase the accuracy of the diagnostic imaging test according to Bayes’ theorem,3 various clinical decision rules have been developed to provide a pretest stratification of risk of DVT. These decision rules combine signs, symptoms, and the presence of risk factors to yield a score to be used to estimate the probability of DVT being present. The most widely used pretest probability assessment tool was developed by Wells and colleagues ~20 years ago.4,5 The rule was tested and validated in the outpatient setting, but is sometimes also used in hospitalized patients. However, in a new cohort study, Silveira et al. assessed the performance of the Wells rule in the inpatient setting, and found that the use of this risk stratification is not safe to rule out DVT or to influence management decisions.6 Wells and colleagues initially identified nine clinical features that were significantly
associated with DVT:5 eight positive variables that included three risk factors for DVT (active cancer; paralysis, paresis, or recent plaster immobilization of the lower extremities; and recently bedridden for ≥3 days, or major surgery within the previous 12 weeks requiring general or regional anaesthesia) and five signs suggestive of DVT (localized tenderness along the distribution of the deep venous system, entire leg swollen, calf swelling ≥3 cm larger than that on the asymptomatic leg, pitting oedema confined to the symptomatic leg, and collateral superficial veins), and one negative variable (alternative diagnosis at least as likely as DVT). The resulting score was tested in the out patient setting in a pivotal study, in which a reduction in the rates of false-negative and false-positive ultrasonography studies was shown.5 An additional variable—the presence of previously documented DVT—was subsequently added to the clinical model.7 This modified model, in combination with the measurement of d‑dimer, was shown to safely reduce the need for ultrasound imaging and to allow a rapid exclusion of DVT in a substantial proportion of patients.7 The results of a number of management studies subsequently confirmed the accuracy of the Wells rule and the safety of withholding anticoagulant therapy in patients with suspected venous thromboembolism on the basis of pretest probability assessment and d‑dimer measurement.8 Clinical guidelines recommend that pretest probability assessment should guide the choice of diagnostic tests in patients with a suspected DVT of the lower limbs, and that no further
NATURE REVIEWS | CARDIOLOGY
testing should be considered in patients with a low pretest probability and a negative d‑dimer measurement.9 However, concerns existed about the validity of pretest probability assessment in particular subgroups of patients. For example, the accuracy of the Wells rule might be reduced in patient groups at high risk of DVT, such as in patients with cancer or in hospitalized patients, because the actual prevalence of DVT is expected to be higher in these groups. Another possible concern related to the accuracy of the assessment when performed by different specialists, such as primary care physicians and hospitalbased emergency doctors. To address these important issues, Geersing et al. carried out a meta-analysis of individual patient data from 13 studies and published their findings in 2014.10 The investigators confirmed that, in general, the probability of DVT is extremely low in patients determined to have low pretest probability using the Wells rule and with a negative d‑dimer measurement, and that this finding applies to patients presenting in primary as well as in hospital care.10 However, they also showed that this combination of tests was inaccurate and, therefore, unsafe in patients with cancer; in this population, the incidence of DVT was 2% in the ‘low-risk’ group, with the upper limit of the 95% confidence interval exceeding 8%.10 As explained by the study
BSIP SA/Alamy
VENOUS THROMBOEMBOLISM
ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS investigators, the pretest probability of DVT in patients with cancer is higher than in patients without cancer, reducing the negative predictive value of pretest probability assessment.10 None of the studies selected for this meta-analysis included inpatients and, therefore, no conclusions on the safety of this approach in this setting could be drawn. In Silveira et al.’s more-recent cohort study to assess the performance of the Wells rule in the inpatient setting, the incidence of DVT in the group of patients determined as having low pretest probability was as high as 6%, with the upper limit of the 95% confidence interval exceeding 11%.6 The area under the curve for discrimination accuracy of the Wells rule in this study was 0.60.6 Therefore, the investigators concluded that the rule “performed only slightly better than chance for discrimination of risk for DVT in hospitalized patients”.6 The findings indicate that the use of the Wells rule in hospitalized patients to exclude the possibility of DVT is not safe and should not influence management decisions. The results of this study confirm that predictive scores should be used only in the populations in which they have been validated. The average risk profile of out patients—in whom the Wells rule was developed and validated—is different from that of an inpatient population.4,5,7 In the first validation study by Wells and colleagues, the proportion of patients with cancer was 13%, and the proportion of patients with recent surgery, paralysis, or recent immobilization (including immobilization with plaster or recently bedridden) was 19%.5 Subsequent studies carried out in the outpatient setting reported very similar figures. Conversely, in the study of inpatients by Silveira and colleagues, the proportion of patients with cancer was nearly threefold higher (37%),
and the proportion of patients with surgery, paralysis, or recent immobilization was more than fourfold higher (89%).6 Another important difference was in the rate of alternative diagnoses that were at least as likely as DVT, which was 48% in studies performed in outpatients10 and 22% in this cohort study of inpatients.6 Consequently, the proportion of patients categorized as being at ‘low risk’ was 55% in the study by Wells et al. and only 11% in the study by Silveira and colleagues, and the proportion of patients categorized as being at ‘high risk’ was 12% and 44%, respectively.5,6 Moreover, 93% of inpatients had elevated d‑dimer levels.6 Surprisingly, despite the higher risk profile of the population enrolled in the study by Silveira and colleagues, the incidence of objectively confirmed DVT was as low as 12%, possibly because of the widespread use of pharmacological prophylaxis in this setting. The use of thromboprophylaxis might also explain the narrow incremental difference in the incidence of DVT across risk groups in the study by Silveira and colleagues—from 6% in the ‘low-risk’ group to 16% in the ‘high-risk’ group.6 In the study by Wells and colleagues, in which we can assume that only a minority of patients was receiving anticoagulation for the prevention of DVT (data not reported), the incremental difference in the incidence of DVT was much broader and ranged from 3% to 75%.5 To conclude, the use of the Wells rule to exclude the possibility of DVT in hospitalized patients is not safe. Until a specifically designed score based on clinical predictors derived from an inpatient population is developed and validated, doctors should refrain from using clinical prediction rules and d‑dimer measurement in hospitalized patients with suspected DVT to drive their diagnostic decisions.
2 | ADVANCE ONLINE PUBLICATION
Department of Clinical and Experimental Medicine, University of Insubria, Viale Borri 57, Varese 21100, Italy. [email protected] doi:10.1038/nrcadio.2015.106 Published online 7 July 2015 Competing interests The author declares no competing interests. 1.
Goodacre, S., Sampson, F., Thomas, S., van Beek, E. & Sutton, A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med. Imaging 5, 6 (2005). 2. Camporese, G. et al. Outcome of patients with suspected lower limb symptomatic deep vein thrombosis and a normal ultrasoundbased initial diagnostic workup: a prospective study. J. Thromb. Haemost. 10, 2605–2606 (2012). 3. Bayes, T. An essay towards solving a problem in the doctrine of chances. Philos. Trans. R. Soc. London 53, 370–418 (1763). 4. Wells, P. S. et al. Accuracy of clinical assessment of deep vein thrombosis. Lancet 345, 1326–1329 (1995). 5. Wells P. S. et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 350, 1795–1798 (1997). 6. Silveira, P. C. et al. Performance of Wells score for deep vein thrombosis in the inpatient setting. JAMA Intern. Med. http://dx.doi.org/ 10.1001/jamainternmed.2015.1687. 7. Wells, P. S. et al. Evaluation of D‑dimer in the diagnosis of suspected deep-vein thrombosis. N. Engl. J. Med. 349, 1227–1235 (2003). 8. Ten Cate-Hoek, A. J. & Prins, M. H. Management studies using a combination of D‑dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J. Thromb. Haemost. 3, 2465–2470 (2005). 9. Bates, S. M. et al. Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141 (Suppl.), e351S–e418S (2012). 10. Geersing, G. J. et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ 348, g1340 (2014).
www.nature.com/nrcardio © 2015 Macmillan Publishers Limited. All rights reserved
