Evaluation of D-dimer Testing Sensitivity and Specificity in Emergency Medicine

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1 Evaluation of D-dimer Testing Sensitivity and Specificity in Emergency Medicine Sayed H. Ebrahim, Bahareh Shafaei, Amindeep Lail, Jennifer Ingersoll, Pratap C. Kumar Department of Cardiology, Jackson Park Hospital, Chicago, IL, United States Abstract Background: The negative value of the D-dimer test has been widely used to rule out thrombotic disorders such as Pulmonary Embolism (PE) and Deep Venous Thrombosis (DVT). Aims: The present study was to evaluate the efficacy of the D-dimer cut-off values based on the patients medical history, symptoms, clinical diagnosis, age and gender, and to correlate the D-dimer value with the necessity of utilizing cost-effective investigations for diagnosing suspected thrombotic disorders. Materials and Methods: Prospective study of 352 patients over 3 consecutive months was conducted. Results: Overall 57.7% of patients had positive D-Dimer values out of which 20.7% were presented with chief complaint of chest pain, 14.8% with Shortness of breath, 7.7% complained of dizziness, 4.5% presented with extremity pain, 4.3% with abdominal pain, 4.3% with flu-like symptoms and cough, and 1.4% presented with alcohol intoxication with non specific complaints. Majority of patients were ultimately diagnosed with non specific chest pain, CHF, respiratory disorders, musculoskeletal disorders, etc. Only 3.125% of patients with positive d-dimer values were diagnosed with either PE or DVT. Conclusion: Low sensitivity and low positive predictive value have strongly suggested an elevated D-dimer neither indicates a specific disease nor has a strong correlation with the clinical severity of the disease. Slight elevation of D-dimer can be justified based on race, age, gender, medical history, initial presentation of patient and clinical diagnosis, and should not cloud the clinical judgment, exposing the patient to redundant and costly investigations. Keywords: D-dimer, DVT, Pulmonary embolism, Sensitivity, Specificity, Thrombotic disorders. Address for correspondence: Bahareh Shafaei, Jackson Park Hospital, 7531 S Stony Island Ave Chicago, IL 60649, United States. baharehs1@gmail.com Introduction Plasma D-dimers are cross-linked fibrin derivatives produced when fibrin is degraded by plasmin (1). It is a direct product of fibrinolysis and indirect product of coagulation. It has a halflife of roughly eight hours (2). D-Dimer level is useful for ruling out both Pulmonary Embolism (PE) and Deep Venous Throm (DVT) for the reason that they are a product of fibrin degradation and are thought to indicate endogenous fibrinolysis in the presence of intravascular thrombosis (3). It increases in Electronic copy available at:

2 many physiological and pathological conditions Currently, more than 30 different assays exist (see table 1) (3,4,5). This gives the test poor for measuring D-dimer and different ranges are sensitivity; however, it has a negative predictive value of approximately 95% for ruling out PE and DVT. Diseases such as PE and DVT, if not detected early, might lead to serious complications including death. Prompt identification entails a high degree of clinical skills and necessary investigations that are both specific and sensitive. The D-dimer is frequently used in the ER to aid in the diagnosis and management. The single test costs $ USD which makes it costly for a test with such poor specificity. The current approach to assist suggested as normal values values (10,11). Thus, a well defined cut-off value is needed. Relying on the manufacturer s recommended suggestion is another issue regarding the D-dimer evaluation which further reduces the reliability of the test as a screening tool. It is essential to understand that the use of the D- dimer test for investigating patients for suspected thrombotic events is only significant if the test is validated for use in the clinical setting. D-dimer assay sensitivity differs among the different testing processes; the test is more in the diagnosis of PE and DVT are the Wells sensitive using ELISA assays (12). Highly and Geneva scores, generated based on clinical presentation of the patient. The score can aid to minimize the number of unnecessary tests which expose the patients to risks and deplete health sensitive assays have been frequently shown to allow exclusion of venous thromboembolism when D-dimer levels are normal, without further imaging. A well-accepted normal range normal care system resources. The revised Geneva D-dimer result (< or =250 ng/ml DDU; < or screening criteria, also based on clinical elements, are used by many hospitals due to the fact that the tests and conditions that are required by Wells and Geneva scores cannot always be satisfied (9). =0.50 g/ml FEU) has a negative predictive value of approximately 95% for the exclusion of acute PE or DVT when there is low or moderate pretest PE probability based on clinical screening scores. Gibson et al stated that Electronic copy available at:

3 patients with likely clinical probability should undergo further testing, regardless of the D- dimer test outcome (13). The aim of this paper is to investigate the sensitivity and specificity of the D-dimer in Emergency Medicine and to evaluate its efficiency on the management of patients. Table 1: Conditions associated with elevated D-dimer Some Physiological and Pathological conditions associated with increased D-dimer value Materials and Methods Subjects and Data Collection This is a prospective research study conducted on 352 African American patients between March 2013 and June 2013 in Jackson Park Hospital, Chicago, IL, United States. Prior to the sample collection, approval from institutional ethical committee and written informed consent from patients were obtained. Deep venous thrombosis/ Pulmonary embolism Arterial thromboembolism/ Aortic dissection Malignancy Disseminated intravascular coagulation (DIC) Catheters /Pacemakers/ Artificial Valves Cardiologic/ Renal and Liver diseases Sever anemia (specifically sickle cell crises) Chronic Respiratory disease (e.g. sever COPD, Emphysema) Eclampsia and Pre-eclampsia Heart failure/ Atrial fibrillation/ MI Stroke / Peripheral artery disease Surgery/ Trauma Infection/ Inflammation Pregnancy Hemodyalisis Musculoskeletal disorders such as Osteoarthritis and immobility Substance abuse Active or recent bleeding/ Ischemia/ Necrosis In order to reduce the confounding factors we excluded the non-african American patients from our data since more than 99% of patients were of African American Origin. Investigations have shown that the Ddimer test commonly was ordered within the first 15 orders (majority within the first 5 orders) in the Emergency Department. The study was based on HemosIL assay of D- dimer, ordered specifically in the hospital s emergency department over a 14-weeks period starting from March D-dimer levels were recorded and tabulated as seen in Figure 1. Subsequent tests ordered after the results of the D-dimer were available included various

4 NUmber of Patients imaging studies such as Doppler, CT scan of the thorax with contrast, echocardiogram, ultrasound and X-ray. Simultaneous laboratory tests such as cardiac enzymes and TSH were also noted. Some cases also required other tests including but not limited to Electroencephalogram (EEG), Kidneys, ureters, and bladder x-ray (KUB). Patient chief compliant and admitting diagnosis information were added which formed Figure 2 and Figure 3 respectively. In order to minimize bias there was no exclusion criteria. It is important to cite lipemia and prestudy use of heparin in patients with suspected DVT or PE can interfere with the D-dimer assay, occasionally causing an under-estimation of the D-dimer level. Therefore, results from lipemic specimens and those taken post-heparin use should be interpreted with caution (14,15). Statistical analysis Microsoft Excel 2010 was used to analyze the data using Statistical Product and Service Solutions (SPSS) statistics for Windows, and tables were created and the data were demonstrated in terms of proportion, mean, standard deviation where applicable. To analyze relationships between biochemical parameters, Pearson correlation coefficients were calculated. The level of significance was considered as P value < Results Total of 352 patients were investigated in this study, out of which 59.4% were female and 40.6% were male. The mean age was 53 years with a standard deviation of 17.2 years. Overall, 56.5% had positive D-dimers with hospital laboratory s cut-off value of 0.50 mcg/ml DDU. Figure 1: D-dimer Levels < >1.2 Series Version (Chicago: SPSS Inc). Pie charts

5 From Figure 1, it can be seen that of the total number of patients, 52 patients had a D-dimer of less than 0.25 mcg/ml, 97 patients had a D- dimer value between mcg/ml and 98 patients had a D-dimer value between mcg/ml. It was found that 29.8% ( 105 patients) of the patients in the study had a D-dimer value symptoms, 71.4% of those patients had positive D-dimer values recorded. Finally from 12 patients who presented with signs of alcohol/drug intoxication; 41.7% of these patients also had an elevated D-dimer value. Figure 2 represents the patients chief compliant upon arrival to the emergency department. greater than 1.1 mcg/ml. Symptom based analysis showed D-dimer was Figure 2: Patient's Chief Complaint ordered for patients presenting with chest pain, shortness of breath, dizziness, abdominal pain, alcohol intoxication with non specific complaints and upper or lower extremity pain. Out of all patients, 150 presented with chest pain 29% 13% 6% 3% 6% 43% Limb Pain Chest Pain Abdominal Pain Intoxication SOB Dizziness and among those, 48.7% had positive D-dimer values. There were 81 patients who presented with shortness of breath, of which 64.2% had positive d-dimer. Fourty four patients presented with dizziness and 61.4% of those patients had above-normal D-dimer values. Twenty two patients presented with abdominal pain of which 68.2% had a positive D-dimer. Twenty one patients presented with limb pain of which 76.2% had positive D-dimer value. Twenty one patients complained of cough and flu-like Diagnosis based analysis showed patients were diagnosed ultimately with non specific chest pain, nonspecific shortness of breath, syncope, chronic obstructive pulmonary disease (COPD),Congestive heart failure (CHF), asthma, cocaine and alcohol intoxication, non specific edema, respiratory failure, sepsis, pregnancy and remaining with other disorders including but not limited to; osteoarthritis, anemia, chronic

6 kidney disease, benign prosthetic hyperplasia, psychiatric disorders and hypertensive heart disease. It was found that 135 patients were diagnosed with chest pain not otherwise specified, of which 47.4% were found to have a high D-dimer level. Twenty one patients were diagnosed with were diagnosed with dizziness and giddiness, of which 37.5% had an abnormal D-dimer. Seven patients were diagnosed with sepsis, of which 71.4% had a high D-dimer. Figure 3: Patient's Final Diagnosis Chest Pain NOS shortness of breath of which 66.7% had an sob elevated D-dimer. There were 19 patients who were diagnosed with syncope and 63.2% of them had a high D-dimer. Nineteen patients syncope copd were diagnosed with COPD of which 73.7% had an above-normal D-dimer. Fifteen patients were diagnosed with CHF, and 66.7% had a high D-dimer. Thirteen patients were diagnosed 2% 2% 2% 2% 21% 4% 4% 4% 5% 5% 6% 38% chf asthma cocaine edema with asthma, and 38.5% of them had an out-ofrange D-dimer. Twelve patients were diagnosed with cocaine-induced chest pain, of which 25.0% of them had a high D-dimer. Nine patients were diagnosed with edema, and 66.7% 2% 3% alchol intoxication respiratory failure dizziness & giddiness sepsis had a high d-dimer. Eight patients were pregnancy diagnosed with alcohol intoxication, of which 50.0% had an elevated d-dimer. Eight patients were diagnosed with respiratory failure, of which 87.5% had a high D-dimer. Eight patients other Finally, seven patients were diagnosed with pregnancy, of which 85.7% had a high D-dimer. For the purpose of this paper the rest of the

7 diagnoses were organized under an other category. 63.2% of these patients were recorded to have a high D-dimer. Figure 3 represents the patients specific diagnosis. Discussion The use of D-dimer assay in conjunction with clinical screening tests is an effective method to treatment of PE and DVT, thus after an initial clinical exam, it is up to the individual Emergency Medicine practitioners to decide on the basis of clinical suspicion which tests to order and the degree of invasiveness to which they will subject patients. In contrast to the V/Q or CT scan, the D-dimer test does not require a specialized radiology technician or aid in diagnosis of PE and DVT in an mandatory exposure of the patient to radiation Emergency Room setting; however due to the non-specific nature of the test, careful parameters must be set in order to maximize the test s negative predictive value. The Wells criteria, for example, has been available for well over a decade and allows categorization of patients into low, moderate, and high risk categories based on a combination of symptoms and history. The categorization of a patient into a low risk category in addition to a negative D-dimer test is reported to have a 99% negative predictive value of DVT in patients aged 60-80, but then drops to a 21-31% NPV in patients aged greater than 80 and intravenous contrast material, however the cut-off value for what constitutes a negative test is a topic of debate. The HemosIL D-dimer assay used at Jackson Park Hospital has a manufacturer-recommended a cut-off value of 0.5 mcg/ml Fibrinogen Equivalent Units (FEU); D-dimer values higher than this number are considered positive indicating that there is a likelihood that the patient has had a thrombotic event, while values lower than 0.5 mcg/ml DDU help to rule out such diagnoses. When the cut-off is set at 0.5 mcg/ml, the D-dimer is positive in 199 patients or 56.5% of the study population. Given that years (16,17). In most emergency departments there were 11 patients who were ultimately there are no specific protocols for diagnosis and diagnosed with either a PE or DVT, this still

8 leaves 153 patients in whom the D-dimer was positive though not indicative of a VTE. Another way to look at this is that with a cut-off of 0.5 mcg/ml DDU, the positive predictive value of the D-dimer test is only 5.5%. The clinical significance is the subsequent testing those 199 patients underwent, such as carotid & lower venous Doppler studies (Cost of $ and $573.80, respectively) or CT scan (Cost of $3,427.60). When the D-dimer is ordered as an initial test in patients with symptoms mimicking those of a DVT or PE (as vague as leg pain or shortness of breath), patients are billed a charge of $ for the blood test. Additionally, patients will endure an ER wait-time of approximately 60 minutes for the D-dimer results, which does not narrow down a diagnosis in more than 40% of them. Over the Three months that our study took place $10, worth of D-dimer tests were ordered for 352 patients we followed in which a VTE could not be ruled out based on our current cut-off value. According to a recent study of D-dimer assay in African Americans, study participants had statistically elevated baseline D-dimer values, even when factors such as egfr were controlled. A separate D-dimer which also categorized participants based on race, found that African American patients had grossly elevated D-dimer values (greater than 1.2 mcg/ml) four times more often than non- African American Patients (5). Given that our entire study populations were of African American origin, upon completion of their admission paperwork, we decided to examine the effects applying the race-based D- dimer cut-off value of 1.2 mcg/ml to the data. When this cut-off is applied to the study population, only 103 out of the 352 patients had a positive D-dimer value in contrast to 199 patients when a cut-off of 0.5mcg/mL was used. With nearly 100 less falsely-elevated D-dimer values, the Positive Predictive Value nearly doubles to 10.7%. Clinically this correlates to 28 less chest CT scans, 14 less Doppler exams, and six less VQ scans ordered in the Emergency Department, or a potential reduction in expenses of $107, over the three months or more than $425, over one year. Additionally

9 The number of positive D-dimers drops from 134 to 72 out of the sub-population of 201 patients aged greater than 50 years. When this value is added to the number of patients aged 50-years or younger whose D-dimer was above 0.5 mcg/ml DDU, the total number of positive D-dimers of all ages of 138. The utilization of this formula eliminates over 60 false-positives out of the >50 years age-bracket of 201 patients. The PPV of D-dimer increases intermediately to 8.0%. Table 2: Age specific mean D-dimer levels and perhaps most importantly, raising the cut-off value to 1.2 mcg/ml did not exclude any of the 11 cases of DVT/PE. Next, given that 57% of the patients in the study fell into the age category of > 50 years, we looked at an agebased strategy in order to combat the documented, frequently benign elevation of D- dimer in older patient populations. In a separate study, an age-dependent cut-off formula has been proposed (18) :D-Dimer cut-off (ng/ml) FEU = (age in yrs x10). This formula is used to calculate a D-dimer cutoff value for patients aged greater than 50 years Age Group Mean D-Dimer (19). Taking into consideration that 201 patients of the study population fall into this age bracket, and that only four of the PE/DVT diagnoses fell outside of this age bracket, we chose to explore the effectiveness of this proposed formula when applied to our study population. A standard fixed cut-off of 250 ng/ml FEU or 0.5 mcg/mlddu is used for the study population aged 0-50 years, but then the proposed formula is used to calculate an individualized per-patient cut-off value for the population aged greater than 50 years, based on individual patient age > Cost effective approach Though the increase in positive predictive value is less than the race-based cut-off, it is important to take note that based on this study the patient

10 population (aged >50 years) required the 40 patients had a diagnosis of a respiratory inflammatory condition asthma, respiratory majority of subsequent testing: 39 out of 64 EDordered CT scans or 61.0% ($133,676.40), 29 of the 48 ED-ordered doppler studies or 60.4% ($18,911.65), and 23 of the 28 V/Q scans ordered in the ED or 82.1% ($8,783.70). The use of the formula would have potentially eliminated the need for 15 CT scans, ten Doppler studies, and six V/Q scans or a total of $60, over the three months or almost $250, over one year. The use of the agedependent formula to establish a D-dimer cut-off for patients aged greater than 50 years did not eliminate the D-dimer values of any of the 11 patients with PE/DVT. At a cost of $ and 60 minutes per D- dimer ordered, the effectiveness and usefulness of the test must be taken into consideration (20). Additionally, the causes of a falsely-elevated D- dimer must be taken into consideration and the prevalence of these causes within our typical patient population. Seven of the patients on whom a D-dimer was ordered, had a pregnancyrelated diagnosis and only one patient had a D- dimer value that fell within the normal range. failure or COPD. In consideration of those four categories alone, 13.4% of the study population is statistically more likely to have a falselyelevated D-dimer, regardless of their presenting symptoms. This calls into question the effectiveness or even usefulness of ordering a D-dimer as an initial screening test in patients presenting with DVT/PE-symptoms when they have pre-existing conditions which will quantitatively raise baseline values and make it difficult to utilize the negative predictive value of a normal D- dimer value and clinical screening criteria. Another concern was that of timing. In all of the 352 patients who had D-dimers ordered, 38 patients left against medical advice (AMA) (10.8% of the study population) before all ordered tests and treatment could be completed although the diagnosis was made and the possibility of the DVT/PE were ruled out based on negative D-dimer value, low-clinical probability, CT scan and Doppler studies, one must take into consideration the 60 minutes that elapses while patients must wait for the results

11 of the D-dimer. 20 of the patients who left Vinicius Lins Barros et al (Figure4), and Robert AMA had D-dimers that were greater than 0.5 mcg/ml, over half of this sub-population. Because the value of the D-dimer as a clinical test is only in its negative predictive value, J. Matthews et al (Figure5) for diagnosis of DVT and PE respectively (22,23). Figure 4. Algorithm for the diagnosis of Deep Vein Thrombosis (DVT) for patients in Emergency setting further testing was necessitated in these 20 patients, therefore taking up more time in the emergency department and subsequently less time that could have been spent on tests with more definitive results before the patients left. A reduction in the number of tests necessary and the timing of these tests would help to decrease the waiting time patients experience and thus, the likelihood of patients leaving AMA before the tests could be completed. Figure 5. Algorithm for the diagnosis of Pulmonary Embolism (PE) for patients in Emergency setting Diagnostic Strategy Encountering patients with DVT and/ or PE, the main question raised is; what s the best strategy to diagnose and manage the patient, especially using the most clinically relevant tests in timely fashion with the best diagnostic approach which is also cost efficient (21)?Several protocols have been proposed for diagnosing DVT and PE; among those we would like to recommend the following protocols suggested by Marcio

12 Conclusion Acknowledgments There are many diseases which are associated Authors wish to thank Miss Elizabeth Maynes with a positive D-dimer value. With a low for assistance in collecting the data. positive predictive value, an elevated D-dimer neither indicates a specific disease nor has a strong correlation with the clinical severity of the disease. Prior to ordering this test and subjecting the patient to additional unnecessary tests, the risks vs. benefits of this test should be considered. Whether due to litigious paranoia or a neglect of the art of clinical diagnosis as culprits, the D-dimer assay is used as an investigating tool without sufficient clinical justification or clinical information such as pretest disease probability, resulting in misuse of the resources and dissipation of assets. Utilizing well-defined testing parameters or an estimation of the clinical probability of a specific presentation in conjunction with strong clinical judgment is essential before ordering the test. For high-risk patients and for those whom the clinical probabilities of DVT or PE are judged effectively, the D-dimer test can be used efficiently to safely exclude those specific References 1- Ghanima, W., Abdelnoor, M. & Holmen, L.O. (2006), D-dimer level is associated with the extent of pulmonary embolism.elsevier,120( ). 2- Bounameaux, H., D-dimer for Exclusion of Venous Thromboembolism. BIOMERIEUX, Koracevic, G.P. (2009), Pragmatic Classification of the Causes of High D-dimer. The American Journal of Emergency Medicine,27(1016.e e7). 4- Chopra, N., Doddamreddy, P. & Grewal, H. (2012), An elevated D-dimer value: a burden on our patients and hospitals. International Journal of General Medicine,5(87 92). 5- Kabrhel, C., Courtney, M. & Camargo, C.A. (2010), Factors Associated With Positive D- dimer Results in Patients Evaluated for Pulmonary Embolism. Society for Academic Emergency Medicine,17( ). 6- Uchiba M, Okajima K. [Fibrinopeptide A (FPA), fibrinopeptide B (FPB) and fibrinopeptide Bbeta(15-42) (FPBbeta15-42)]. Nihon Rinsho Dec;62 Suppl 12: Perrier A. D-dimer for suspected pulmonary embolism: whom should we test? Chest 2004;125(3): Miller A. C. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003;58 (6): Righini M, Perrier A, De Moerloose P, Bounameaux H. D-dimer for venous thromboembolism diagnosis: twenty years diseases only.

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