The current scenario-analysis determined the theoretical failure-rate and efficiency of a diagnostic strategy using the Wells CDR at different cut-off values combined with a qualitative POC D-dimer test for excluding PE in primary care. Excluding PE safely in primary care with a CDR and a point-of-care D-dimer test seems feasible. However, the strategy appeared to be safe only when the cut-off value of the Wells-CDR was lowered to <2 using the SimpliRed and 0 using the Simplify D-dimer test, respectively. Efficiency is considerably lower when using those cut-off values: the number of patients that need referral is 76.2% and 87.6% respectively, as compared to 65% with the Wells cut-off value of ≤ 4 in the Christopher-study.
Several aspects of this analysis require comment.
Firstly, we based the analysis on the test characteristics of two qualitative POC-D-dimer tests as reported in a diagnostic meta-analysis. In this meta-analysis most of the studies included patients suspected of DVT. Only six studies included patients with PE. However in a covariate analysis of studies with only DVT both the sensitivity and the specificity of the SimpliRed and the Simplify D-dimer test were essentially the same as in the overall analysis.
Secondly, several studies performed in secondary care (PE-prevalence ranging from 3.8-10%) show that a strategy using a CDR and a qualitative POC- D-dimer test can be used safely to exclude PE. Moreover these studies show a good efficiency ranging from 44-66% [7, 10–13]. Wells et al were the first to show that the combination of Wells CDR <2 and a negative D-dimer test was safe to exclude PE. (prevalence 9.5%, failure rate 0.2%, efficiency 47%) [7]. According to Hogg and co-workers the Simplify D-dimer test alone was not sufficiently sensitive (sensitivity 81.8%, specificity 74.2%) to exclude PE in low-risk patients (prevalence PE 5.3%) presenting to the emergency department (ED) with pleuritic chest pain. However, when the Simplify D-dimer test was combined with a low-clinical probability Wells-rule the negative predictive value of the combined test was 99.3% (CI 97.4-99.9%): high enough to exclude PE safely [10]. Kline et al showed in low-risk ED-patients (prevalence PE 4.7%) that combination of a physician's unstructured estimate of pre-test probability of PE of <15% and a negative Simplify-D-dimer test excluded PE safely (sensitivity D-Dimer-test 80.6%, specificity 72.5%) [11]. In a primary care based management study sensitivity of the Simplify D-dimer test proved to be sufficient to exclude deep vein thrombosis (DVT) safely in patients with a low clinical probability. The relatively higher specificity, as compared to laboratory based quantitative D-dimer tests provided a good efficiency [14].
Although the sensitivity of the Simplify D-Dimer test in the studies of Hogg and Kline was only 81.8% and 80.6%, respectively, the negative predictive value of the combined strategy using a pre-test probability assessment and the Simplify D-Dimer test was high enough to exclude PE safely due to the low PE-prevalence in these studies.
Thirdly, a weak point of the analysis is that although we have excluded all in-patients the study-population is still not really a primary care population. The outpatients included in the Christopher-study are likely selectively biased as the primary care physician used his own judgement before referring the patient. In the Christopher-study the PE-prevalence was 20.2%. In daily practice when a primary care physician will use the Wells-CDR rule combined with a POC D-dimer test the prevalence of PE in suspected patients is expected to be lower which will improve the negative predictive value (and thereby safety and efficiency) of an exclusion strategy for PE in primary care.
Fourthly, we don't know how well the Wells CDR would perform in primary care. In secondary care the Wells rule is usually applied after routine blood tests, chest radiography and electrocardiography. The primary care physician is usually lacking this information and this will clearly influence the scoring of the subjective variable 'pulmonary embolism is as likely as or more likely than an alternative diagnosis'.
Fifthly, we know that the test characteristics of the POC-D-dimer test, unlike this scenario, are not fixed but are influenced by the prevalence of PE in the different Wells-groups. It is likely that the specificity of the D-dimer test will increase as the prevalence decreases. This might improve the negative predictive value of the strategy in primary care [17, 18].
Sixthly, in this analysis the SimpliRED D-dimer assay was used which has certain limitations. It is known that this method may be associated with a risk for inadequate interpretation due to the fact that the results are based on a subjective interpretation of the presence or absence of agglutination [19]. This risk for inadequate interpretation will be enhanced by infrequent use of the assay. An average Dutch primary care physician will use a POC D-dimer assay for exclusion of PE only 3-5 times a year. However the physician will use the same assay also for exclusion of DVT [14]. We expect the Dutch primary care physician to apply the POC D-dimer test 12-15 times a year in both suspected PE-patients as DVT-patients. We think this will justify an adequate and reliable use of the assay.
Finally, although in scenario 2 (Simplify) the point estimate failure rate in Wells CDR < 2 is within the safety limits, the upper confidence limit exceeds 2.7%. Confidence intervals become larger with decreasing number of patients. It can be expected that with an increasing number of patients the proportion in the lower Wells-CDR score will be higher and the confidence interval will become narrower. Therefore scenario 2 might also be safe in Wells <2.
In secondary care, in a strategy using a more sensitive, quantitative D-dimer test, a cut-off value of Wells ≤ 4 is generally accepted as safe. Although the sensitivity of the POC qualitative D-dimer test is lower, the specificity of the test is higher and as a consequence efficiency is higher at the cost of safety. Recalibration of the Wells-rule for a primary care situation might overcome the safety problems.