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Three Part Question

In a [patient with a suspected DVT] does the [SimpliRed test] reliably [rule out the diagnosis]?

Clinical Scenario

A patient attends the Emergency Department with signs and symptoms consistent with a Deep Venous Thrombosis. Somebody suggests that there is a new bedside blood test, called SimpliRed, that may help to rule out the diagnosis in your patient. You know that ruling out a diagnosis is possible by having a test with a high sensitivity or negative predictive value. You wonder what evidence there is to suggest that SimpliRed fulfils these criteria?

Search Strategy

Medline 1966-11/00 using the OVID interface.
{[(exp thrombosis OR exp venous thrombosis OR thrombosis.mp OR venous thrombosis.mp OR deep venous thrombosis.mp) AND (exp fibrin fibrinogen degradation products OR simplired.mp OR d-dimer$.mp)] LIMIT to human and English} OR Medline 1966-11/00 using OVID interface. simplired.mp.

Search Outcome

741 and 37 papers found of which 13 were relevant and of sufficient quality. These 13 remaining papers are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Wells PS et al, 1995, Canada	214 consecutive patients referred for investigation of ?DVT	Prospective cohort	Prevalence	25%	No sample size calculation Excluded patients with inconclusive venograms or plethysmogram
			Sensitivity	88% (CI 77-96)
			Specificity	77% (CI 63-80)
			Negative predictive value (NPV)	95% (CI 89-98)
			Likelihood ratio for negative result (NLR)	0.16
Brenner B et al, 1995, Israel	86 consecutive patients referred for investigation of ?DVT	Prospective cohort	Prevalence	58%	Small patient numbers No sample size calculation No confidence intervals
			Sensitivity	94%
			Specificity	61%
			NPV	88%
			NLR	0.1
Turkstra F et al, 1996, Netherlands	234 consecutive patients referred for ?DVT or ?PE	Prospective cohort	Prevalence	27%	No sample size calculation (but good numbers)
			Sensitivity	100% (CI 95-100)
			Specificity	58% (CI 50-65)
			NPV	100% (CI 96-100)
Janssen MC et al, 1997, Netherlands	132 patients referred to ED or OPD for investigation of ?DVT	Prospective cohort	Prevalence	67%	No sample size calculation Technique of assay may have affected results Reference standard not applied to all patients
			Sensitivity	61% (CI 51-71)
			Specificity	90% (CI 81-99)
			NPV	52% (CI 29-75)
			NLR	0.43
Ginsberg JS et al, 1997, Canada	398 consecutive patients referred to thromboembolic OPD as first episode of ?DVT	Prospective management study	NPV D-dimer alone	97.1% (CI 94.5 –98.8)	No sample size calculation Reference standard not applied to all patients
			NPV D-dimer and plethysmography together	98.5% (CI 96.3 – 99.6)
Mayer W et al, 1997, Austria	108 consecutive patients referred to vascular laboratory as ?DVT	Prospective cohort	Prevalence	31%	Small patient numbers No sample size calculation Used single ultrasound as reference standard
			Sensitivity	100% (CI 89-100)
			Specificity	75% (CI 63-84)
			NPV	100% (CI 94-100)
Wildberger JE et al, 1998, Germany	250 consecutive patients referred for venography	Prospective cohort	Sensitivity	96%	No sample size calculation Patient selection bias No confidence intervals
			Specificity	59%
			NPV	97%
			NLR	0.06
Wells PS et al, 1998, Canada	496 consecutive outpatients referred with ?DVT	Prospective cohort	Overall sensitivity	94%	No sample size calculation Patient selection bias No confidence intervals
			Overall specificity	71%
			NPV	98% (CI 96-99)
			NLR	0.08
			Low pretest probability:
			Sensitivity	87%
			Specificity	76%
			NPV	99% (CI 97-100)
			NLR	0.17
			Medium pretest probability:
			Sensitivity	89%
			Specificity	64%
			NPV	97% (CI 90-99)
			NLR	0.17
			High pretest probability:
			Sensitivity	98%
			Specificity	54%
			NPV	86% (CI 42-97)
			NLR	0.04
Mauron T et al, 1998, Switzerland	45 consecutive outpatients referred with ?DVT	Prospective cohort	Prevalence	33%	Small patient numbers No sample size calculation Wide confidence intervals
			Sensitivity	53% (CI 28-78)
			Specificity	70% (CI 54-86)
			NPV	75% (CI 59-91)
			NLR	0.67
Carter CJ et al, 1999, Canada	200 consecutive patients referred to diagnostic radiology department with ?DVT Inpatients and outpatients	Prospective cohort	Prevalence	28%	No sample size calculation Used single ultrasound as reference standard Wide confidence intervals
			Sensitivity	87% (CI 80-96)
			Specificity	79%
			NPV	94%
			NLR	0.16
Lennox AF et al, 1999, UK	200 consecutive patients referred to diagnostic radiology department with ?DVT Inpatients and outpatients	Prospective cohort	Prevalence	23%	No sample size calculation Incorrect test procedure likely to give falsely high sensitivities No confidence intervals
			Sensitivity	91%
			Specificity	82%
			NPV	97%
			NLR	0.11
Farrell S et al, 2000, USA	173 consecutive patients referred to ED with ?DVT (48) or ?PE (125)	Prospective clinical trial	Prevalence	33%	Did not recruit all patients required Used single ultrasound as reference standard Wide confidence intervals
			Sensitivity	56% (CI 32-81)
			NPV	77% (CI 62-92)
			NLR	0.61 (CI 0.34 -1.11)
van der Graaf F et al, 2000, Netherlands	112 outpatients referred to department	Prospective cohort	Prevalence	50%	Small patient numbers No sample size calculation Wide confidence intervals
			Sensitivity	80% (CI 66-90)
			Specificity	94% (CI 83-99)
			NPV	82% (CI 70-91)
			NLR	0.21

Comment(s)

The "gold standard" investigation for DVT is contrast venography. This has now been replaced in many centres with a strategy of single or serial compression ultrasound, hence the use of different reference standard tests. If an investigation is to be used in order to rule out a diagnosis, then it must have a sensitivity of 95% or above. In some of the studies mentioned this is the case, however such is the variability of the results obtained in the other studies the safety of SimpliRed as a lone exclusionary test must be in question. The reasons for this variability may include the operators of the assay or the various techniques used. Many of the results however are still inadequate.

Clinical Bottom Line

It is not safe to use SimpliRed as a lone exclusionary test for a patient presenting to the Emergency Department with a possible DVT.

References

1. Wells PS, Brill-Edwards P, Stevens P, et al. A novel and rapid whole-blood assay for D-dimer in patients with clinically suspected deep vein thrombosis. Circulation 1995;91(8):2184-7.
2. Brenner B, Pery M, Lanir N, et al. Application of a bedside whole blood D-dimer assay in the diagnosis of deep vein thrombosis. Blood Coag Fibrinol 1995;6(3):219-22.
3. Turkstra F, van Beek EJ, ten Cate JW, Buller HR. Reliable rapid blood test for the exclusion of venous thromboembolism in symptomatic outpatients. Thromb Haemost 1996;76(1):9-11.
4. Janssen MC, Heebels AE, de Metz M, et al. Reliability of five rapid D-dimer assays compared to ELISA in the exclusion of deep venous thrombosis. Thromb Haemost 1997;77(2):262-6.
5. Ginsberg JS, Kearon C, Douketis J, et al. The use of D-dimer testing and impedance plethysmographic examination in patients with clinical indications of deep vein thrombosis. Arch Int Med 1997;157(10):1077-81.
6. Mayer W, Hirschwehr R, Hippmann G, et al. Whole-blood immunoassay (SimpliRED) versus plasma immunoassay (NycoCard) for the diagnosis of clinically suspected deep vein thrombosis. Vasa 1997;26(2):97-101.
7. Wildberger JE, Vorwerk D, Kilbinger M, et al. Bedside testing (SimpliRED) in the diagnosis of deep vein thrombosis. Evaluation of 250 patients. Invest Radiol 1998;33(4):232-5.
8. Wells PS, Anderson DR, Bormanis J, et al SimpliRED D-dimer can reduce the diagnostic tests in suspected deep vein thrombosis [letter]. Lancet 1998;351(9113):1405-6.
9. Mauron T, Baumgartner I, Z'Brun A, et al. SimpliRED D-dimer assay: comparability of capillary and citrated venous whole blood, between-assay variability, and performance of the test for exclusion of deep vein thrombosis in symptomatic outpati Thromb Haemost 1998;79(6):1217-9.
10. Carter CJ, Serrano K, Breen DJ, et al. Rapid fibrin D-dimer tests for deep venous thrombosis: factors affecting diagnostic utility. J Emerg Med 1999;17(4):605-10.
11. Lennox AF, Delis KT, Serunkuma S, et al. Combination of a clinical risk assessment score and rapid whole blood D-dimer testing in the diagnosis of deep vein thrombosis in symptomatic patients. J Vasc Surg 1999;30(5):794-803.
12. Farrell S, Hayes T, Shaw M. A negative SimpliRed D-dimer assay result does exclude the diagnosis of deep venous thrombosis or pulmonary embolus in emergency department patients. Ann Emerg Med 2000;35(2):121-5.
13. van der Graaf F, van den Borne H, van der Kolk M, et al. Exclusion of deep venous thrombosis with D-dimer testing – comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard. Thromb Haemost 2000;83(2):191-8.