Assessment of the current D-dimer cutoff point in pulmonary embolism workup at a single institution: Retrospective study.

Background: The currently used D-dimer (DD) cutoff point is associated with a large number of negative CT-pulmonary angiographies (CTPA). We hypothesized presence of deficiency in the current cutoff and a need to look for a better DD threshold. Materials and
Methods: We conducted a retrospective medical records analysis of all patients who had a CTPA as part of pulmonary embolism (PE) workup over a 1-year period. All emergency room (ER) patients who had DD assay checked prior to CTPA were included in the analysis. We assessed our institutional cutoff point and tried to test other presumptive DD thresholds retrospectively.
Results: At our institution 1591 CTPA were performed in 2014, with 1220 scans (77%) performed in the ER. DD test was ordered prior to CTPA imaging in 238 ER patients (19.5%) as part of the PE workup. PE was diagnosed in 14 cases (6%). The sensitivity and specificity of the currently used DD cutoff (0.5 mcg/mL) were found to be 100% and 13%, respectively. Shifting the cutoff value from 0.5 to 0.85 mcg/mL would result in a significant increase in the specificity from 13% to 51% while maintaining the same sensitivity of 100%. This would make theoretically 84 CTPA scans, corresponding to 35% of CTPA imaging, unnecessary because DD would be considered negative based on this presumptive threshold. Conclusions: Our results suggest a significant deficiency in the institutional DD cutoff point with the need to find a better threshold through a large multicenter prospective trial to minimize unnecessary CTPA scans and to improve patient safety.

Background

Pulmonary embolism (PE) has an approximate incidence of 70 per 100000 every year, and mortality rate of 15% in the first 90 days post diagnosis.[123] It has a variety of nonspecific presentations which make the diagnosis challenging.[4] Computed tomographic pulmonary angiography (CTPA) has evolved as the new reference gold standard tool in evaluating patients with suspected PE.[345] However, the drawbacks of CTPA ought to be taken in consideration during PE workup such as radiation exposure, contract-induced nephropathy (CIN), and high cost.[67] Therefore, evidence-based guidelines recommend using one of the validated score systems (Wells or Geneva criteria) to assess pretest probability (PTP) of PE and utilizing D-dimer (DD) testing in excluding PE for patients with low PTP.[891011]

DD is a degradation product from cross-linked fibrin due to plasmin-mediated fibrinolysis.[12] Enzyme-linked immunosorbent assay (ELISA) and latex-based automated immunoturbidimetric assay were found to be the most sensitive quantitative methods to measure the DD values.[13] The reference laboratory ranges of DD assay are either less than 0.5 mcg/mL Fibrinogen Equivalent Units (FEU) or less than 0.25 mcg/mL D-dimer Units (DDU).[14] PE was found to result in a significant increase in DD.[15] However, DD can also be elevated in other conditions with a high fibrin turnover such as aging, pregnancy, surgery, immobility, active malignancy, sickle cell disease, and inflammatory process; or with a decreased fibrin clearance as end-stage renal and liver diseases.[1316]

At our institution, we noticed that a high number of CTPA scans had been ordered because of a slight increase in DD values. The vast majority of these scans came back negative for PE. Thus, we performed a retrospective analysis on all patients with suspected PE who had both DD and CTPA to demonstrate the deficiencies of the currently used DD cutoff point at our institution.

Materials and Methods

Study design and data collection

We conducted a retrospective study at Allegheny General Hospital (AGH) during a 1-year period from January 1, 2014 through December 31, 2014. AGH is a tertiary care academic center in Pittsburgh, Pennsylvania, with more than 55,000 emergency room visits per year. The Institutional Review Board of AGH granted the permission for our study.

We obtained all cases of CTPA scans performed during the study time frame from a radiology registry. Thereafter, we extracted emergency room (ER) patients who had DD assay checked prior to CTPA as part of their PE workup. Our investigators retrospectively reviewed patient charts and collected relevant data including patient demographics (age, gender, and race), DD values, and CTPA results.

CTPA imaging was labeled as positive and negative for acute PE based on an independent interpretation by board-certified chest radiologists. DD measurements at AGH were reported in fibrinogen equivalent units as micrograms per milliliter (mcg/mL) using automated immunoturbidimetric method, with normal DD reference of <0.5 mcg/mL.

Outcome

The study was performed to retrospectively assess the sensitivity and specificity of the current institutional DD cutoff point and to compare its efficacy with other presumptive DD cutoff points. Thus, we tried to examine the sensitivity and specificity of different theoretical DD thresholds which are higher than 0.5 mcg/mL in a retrospective nature. The best DD threshold was defined as a DD value which maintains the same sensitivity of the current DD cutoff but the least false positive rate. In addition, the newly recommended age-adjusted DD cutoff point (age × 0.01 mcg/mL FEU)[17] was retrospectively applied on our sample to compare it with our institutional DD cutoff.

Statistical analyses

The Statistical Package for the Social Sciences (SPSS) version 18 was employed for statistical analyses. Chi-square test was applied in 2 × 2 contingency tables to explore the difference between the categorical variables such as gender, ethnicity, and CTPA results. An unpaired t-test was used to illustrate the associations among the continuous variables such as age and DD values. Receiver-Operator Characteristics (ROC) curve was used to locate the ideal DD cutoff value and to calculate the sensitivity and specificity for all possible threshold points of DD assay. The statistical significance was determined when P values were less than 0.05.

Results

Radiology registry provided 1591 consecutive CTPA cases performed at AGH during the study period; out of which, 1220 scans were ordered in the emergency room (ER). We identified 238 ER patients (19.5%) who had DD test checked prior to CTPA scan as part of their PE workup [Figure 1]. This sample had 148 females (62%) and 158 Caucasians (66%), with an average age of 53 years (18–93 years) [Figure 2].

Figure 1

Study flowchart. CTPA: computed tomographic pulmonary angiography; DD: D-dimer; ER: emergency room; PE: pulmonary embolism

Figure 2

Age distribution in the study sample

PE was diagnosed in 14 cases (6%). Chest pain and dyspnea were the leading complaints for PE workup [Table 1]. DD value was significantly higher among patients with diagnosed PE compared to those who did not have PE; 6.1 mcg/mL versus 1.5 mcg/mL, respectively (P < 0.0001) [Figure 3]. As shown in Figure 3, the majority of false positive DD values were found in the range of 0.51–2.00 mcg/mL.

Table 1

Characteristics of included patients

Characteristics of included patients (n=238)
Characteristics	Patients with PE (n=14) No. (%)	Patients without PE (n=224) No. (%)
Female	8 (57%)	140 (63%)
Age, average (range) in years	54 (25-79)	53 (18 – 93)
Caucasians	9 (64%)	149 (67%)
Chest pain	8 (57%)	125 (59%)
Dyspnea	7 (50%)	76 (34%)
Syncope	1 (7%)	7 (3%)
Hemoptysis	2 (14%)	2 (1%)
Tachycardia	10 (71%)	101 (45%)
Prior history of VTE	2 (14%)	15 (7%)
Active malignancy	1 (7%)	11 (5%)
Recent surgery	2 (14%)	7 (3%)

PE: Pulmonary embolism. VTE: Venous thromboembolism

Figure 3

Distribution of D-dimer values in patients with and without pulmonary embolism. DD: D-dimer; PE: pulmonary embolism

The sensitivity and specificity of the currently used DD cutoff value (0.5 mcg/mL) in our sample were found to be 100% and 13%, respectively. ROC curve was performed for all possible DD cutoff levels with area under the curve of 0.86 (95% confidence interval of 0.77–0.94) [Figure 4]. The analysis suggested multiple cutoff points with different sensitivity and specificity rates as demonstrated in Table 2.

Figure 4

Receiver-Operator Characteristics (ROC) curve for all possible D-dimer cutoff points

Table 2

Suggested D-dimer cutoff points with their sensitivities, specificities, positive and negative predictive values, and false positive rates

Cutoff Point (mcg/mL)	Sensitivity	Specificity	PPV	NPV	False Positive Rate of DD
0.50	100%	13%	6.7%	100%	82%
0.55	100%	20%	7.3%	100%	75%
0.60	100%	25%	7.7%	100%	71%
0.65	100%	30%	8.1%	100%	66%
0.70	100%	36%	8.9%	100%	60%
0.75	100%	44%	10.0%	100%	53%
0.80	100%	48%	10.8%	100%	49%
0.85	100%	51%	11.3%	100%	46%
0.90	93%	54%	11.2%	99.2%	43%
0.95	93%	57%	11.8%	99.2%	41%
1.00	93%	58%	12.0%	99.2%	40%
1.05	93%	59%	12.3%	99.2%	39%
1.10	86%	59%	11.7%	98.5%	38%

PPV: Positive predictive value, NPV: Negative predictive value, DD: D-dimer

Our study revealed that shifting the cutoff value of DD test from 0.5 mcg/mL to 0.85 mcg/mL would result in a significant increase in the specificity from 13% to 51% while maintaining the same sensitivity of 100% and the same negative predictive value (NPV) of 100%. In addition, it was noted that 82% of DD results in our sample were found to be false positive based on the currently used DD cutoff. This percentage would decrease to 46% if the shifted cutoff (0.85 mcg/mL) had been used.

If we assume that we had applied the increased threshold of 0.85 mcg/mL on our sample, this would change the interpretation of 84 D-dimer cases from being “positive” to be “negative” without missing PE. This would presumptively make 84 CTPA scans, corresponding to 35% of all CTPA imaging, unnecessary since DD would be negative based on the shifted cutoff.

On the other hand, we found that applying the validated age-adjusted cutoff point of DD assay on our sample could safely have saved 12 CTPA scans, corresponding to 5% of all CTPA imaging, without missing any single PE case.

Discussion

The need for a new DD threshold in PE workup

Our study revealed that a significant number of negative CTPA scans are performed due to a slight increase in DD value above the traditional cutoff (0.5 mcg/mL). These scans could be avoidable if the cutoff was higher. ROC curve demonstrated a correlation between rising DD cutoff point and a substantial increase in the specificity of this test. Simultaneously, the test's sensitivity had not changed until the cutoff exceeded the value of 0.85 mcg/mL, as shown in Table 2.

Shifting the DD cutoff value from 0.5 mcg/mL to 0.85 mcg/mL not only resulted in almost 4-fold improvement in the test's specificity but it also maintained an optimal sensitivity of 100%. Thus, more than a third of CTPA scans would be presumptively considered unnecessary by applying the shifted threshold of 0.85 mcg/mL. Moreover, the ADJUST-PE study, which is a multicenter multinational prospective trial, had already validated the use of age-adjusted cutoff for DD assay instead of a fixed threshold.[17] Therefore, age adjustment is necessary for any DD cutoff that will be used for PE workup.

There are similar studies that shed light on the importance of moving the DD cutoff point up to a higher level where unnecessary CTPA examinations can be minimized without changing the crucial role of DD in ruling out PE.[1819] However, all of these studies are retrospective reviews with no consensus on a certain fixed value and not taking into consideration the aging factor. Thus, prospective trials are needed to validate using a shifted DD cutoff combined with age adjustment. Such practice will have a momentous impact on patient safety and hospital resources utilization.

Hospital resources overutilization

CTPA imaging is over-utilized and has exponentially increased over the past two decades with decreasing positivity rate.[20212223] Physicians’ noncompliance with evidence-based guidelines was found to be a major contributing factor to CTPA overuse nationwide.[24252627282930313233] In our study, less than 20% of ER patients with suspected PE underwent DD testing prior to CTPA scan. In addition, we found 30 cases (12.6%) where physician proceeded to CTPA despite negative DD. There are several presumptive reasons behind such high noncompliance, which include insufficient training on calculating PTP score, fear of malpractice litigation, or performing additional thoracic imaging to look for an alternative diagnosis.[3435]

On the other hand, DD testing might lead to ordering unnecessary CTPA scans due to its high false positive rate.[36] This has raised the suspicion about the efficacy of the currently used DD cutoff point and the necessity to raise it to a better practical threshold.[373839] In our study, the false positive rate of DD assay decreased by applying retrospectively the age-adjusted DD cutoff on our sample and by making a theoretical threshold of 0.85 mcg/mL.

We believe that improving physicians’ compliance in practicing the evidence-based diagnostic algorithms along with adjusting the DD cutoff point in PE workup would avert performing a lot of unnecessary CTPA imaging. Such changes can aid in reducing patients’ exposure to the disadvantages of this radiologic modality, which include radiation-related cancer risk, CIN, contrast-induced anaphylactic reactions, pulmonary edema, cardiac arrhythmias, and contrast-related death.[404142]

Study limitations

The limitations of our study include the retrospective nature of the analysis and conducting the study at a single medical center. In addition, the study examined DD cutoff points by reviewing CTPA registry without taking into account those who underwent perfusion/ventilation examinations or those who had DD testing and no subsequent imaging during PE workup. Moreover, the study revealed that DD testing was ordered in only 20% of CTPA cases without knowing the reasons behind selecting these cases by ER physicians, which makes us unable to rule out a selection bias in our sample. Thus, it will be difficult to examine the safety and the validation of a new DD cutoff based on the methodology applied in this study. However, our review highlights the deficit in the currently used DD cutoff and the possibility of considering a shifted DD threshold in addition to age adjustment in future trials.

Conclusion

Our data shows a significant deficiency in the currently used DD cutoff point. Applying the age adjusted DD cutoff and testing the safety of a shifted threshold through a large multicenter prospective trial would help in reducing the amount of unnecessary CTPA scans. Such practice can potentially improve patient safety and hospital resources utilization.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.