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2004 - Review: Several factors are associated with the performance of d-dimer assays for detecting deep venous thrombosis | 2004 Nov-Dec : Volume 141, Number 3, Page 76 | ACP Journal Club Archives
Review: Several factors are associated with the performance of D-dimer assays for detecting deep venous thrombosis
In symptomatic patients, what factors are associated with the performance of D-dimer assays for detecting lower-extremity deep venous thrombosis (DVT)?
Study selection and assessment: Diagnostic studies that calculated sensitivities and specificities or provided paired data for comparing D-dimer assay results with lower extremity ultrasonography or venography for detecting acute DVT in symptomatic patients.
Outcome: Diagnostic odds ratio (DOR) as a function of D-dimer assay while controlling for the reference standard, sample size, overall prevalence of disease, and patient mix of each study.
23 studies (3985 patients) met the selection criteria. Groups of D-dimer assays evaluated included first-generation latex agglutination assays (D-dimer test, Dimertest, Dimertest II, and Nephelotex), second-generation latex agglutination assays (Auto Dimertest, BC D-Dimer, IL Test, Liatest, LPIA, Tinaquant, and Turbiquant), membrane ELISAs (Instant I.A. and NyocCard), erythrocyte agglutination assays (SimpliRED), automated rapid ELFA (VIDAS), and microplate ELISAs (Asserachrom, Dimertest EIA, Dimertest GOLD EIA, Enzygnost, and Fibrinostika). Sensitivity varied from 51% to 100% and specificity from 19% to 94%. Multivariate analysis showed that only the Dimertest, NycoCard, and Tinaquant assays differed (all with lower discriminant ability) from the VIDAS assay (Table). Reference standards included ultrasonography (8 studies), venography (7 studies), and a combination of ultrasonography and venography (8 studies). Multivariate analysis showed that choice of venography as the reference standard was associated with better assay performance (Table). 14 of 23 studies were done exclusively in outpatient populations with a prevalence of DVT that ranged from 20% to 68%. The patient population of the other 9 studies was classified as mixed (for data analysis purposes), with 4 studies done exclusively in inpatient populations with a prevalence of 28% to 69%. Multivariate analysis showed that a 10% increase in prevalence of DVT in the study population was associated with poorer assay performance (relative DOR 0.78, {95% CI 0.67 to 0.95}*). However, assay performance in mixed populations did not differ from that in outpatients (relative DOR 0.61, {95% CI 0.29 to 1.31}*).
In symptomatic patients, biochemical and technical characteristics of the assays, disease prevalence, and choice of reference standard are associated with the wide variation in performance of D-dimer assays for diagnosing lower-extremity deep venous thrombosis.
Table. Factors associated with the performance (diagnostic odds ratio [DOR]) of D-dimer assays for detecting deep venous thrombosis in symptomatic patients†
Plasma D-dimer is emerging as a simple biological test that may rule out proximal DVT in selected patients. But an important question remains: In which patients and with what assay should we measure D-dimer?
The meta-analysis by Heim and colleagues highlights some important points on D-dimer research: 1) Study samples are small and include different patient populations; 2) D-dimer assays rely on no less than 6 different laboratory methods; and 3) D-dimer diagnostic characteristics exhibit considerable heterogeneity.
While using DORs allows us to account for those differences in a multivariate model (1), the approach has limitations. The DOR is the ratio of the positive and negative likelihood ratio. Therefore, it is a global index of diagnostic test performance and may be identical for a less sensitive but more specific D-dimer assay and a more sensitive but less specific test. Even the most specific assays are not specific enough to rule in DVT, and D-dimer is only used to rule out DVT in combination with clinical probability. Hence, use of DORs may dampen true sensitivity difference between assays, and this is compounded by the small sample sizes. Be that as it may, as concluded by the authors, each D-dimer assay should be evaluated separately.
The most important evidence on the safety and clinical usefulness of a particular D-dimer assay would stem from well-designed, large-scale, management studies that allow a precise estimate of the 3-month thromboembolic risk in patients left untreated based on a D-dimer result below the cutpoint (2, 3).
In patients at risk for sudden death because of left ventricular systolic dysfunction who have not had life-threatening ventricular arrhythmias, what is the cost-effectiveness of implantable cardioverter–defibrillators (ICDs) compared with control therapy?
Design: Cost-effectiveness analysis from a societal perspective using a decision model based on the individual results of 8 randomized controlled trials (RCTs), with follow-up of 16 to 41 months and lifetime extrapolation.
Patients: Patients at risk for sudden death because of left ventricular systolic dysfunction who had not had life-threatening ventricular arrhythmias. {Patients had a history of myocardial infarction, coronary artery disease, cardiomyopathy, heart failure, or coronary artery bypass graft}*.
Intervention: Prophylactic implantation of an ICD compared with control treatment {usually conventional medical therapy}*.
Outcomes: Incremental cost-effectiveness of ICD per year of life and per quality-adjusted life-year (QALY) with a utility adjustment of 0.88 in both groups. Costs, in 2005 U.S. dollars, were direct costs of medical care, extrapolated until death from any cause.
The cost of ICD implantation was estimated to be $27 975, with replacement after 5 years at a cost of $18 390. In all trials, the lifetime cost with ICD was greater than that with the control treatment (range for the difference $55 700 to $101 500). In 6 RCTs, ICD increased life expectancy and QALY (Table). In these trials, the incremental cost-effectiveness of ICD ranged from $24 500 to $50 700 per life-year gained and from $34 000 to $70 200 per QALY gained. In the 2 other RCTs, ICD did not increase life expectancy and thus was less effective and more expensive than control treatment. In sensitivity analyses, the cost-effectiveness of ICD improved if the efficacy was higher, the cost of the device was lower, the interval until replacement was longer, quality of life was improved, and the benefit of ICD continued throughout life.
In patients at risk for sudden death because of left ventricular systolic dysfunction for whom a device-related reduction in mortality had been shown, prophylactic implantable cardioverter–defibrillators had a cost-effectiveness of $34 000 to $70 200 per quality-adjusted life-year gained.
Sources of funding: Blue Cross Blue Shield Association Technology Evaluation Center; Department of Veterans Affairs; Agency for Healthcare Research and Quality.
Table. Range of health and economic outcomes of implantable cardioverter–defibrillators (ICDs) vs control treatment (conventional medical therapy), extrapolated to lifetime, from 6 trials that showed efficacy of ICDs
Cardiovascular medicine is at the threshold of moving from an era of scientific and technical limitations to an era of economic limitation. Prophylactic ICD therapy stands as a stark test of how scientific, political, and economic forces will resolve this threshold in the United States and elsewhere.
Sanders and colleagues accurately summarize the clinical and economic RCT data in the form of a cost-effectiveness analysis. Prophylactic ICD placement, in patients without documented ventricular arrhythmia but with significant left ventricular systolic dysfunction, increases average life expectancy by 2.1 to 6.2 undiscounted years (or 1.5 to 4.5 QALYs). The incremental increase in estimated lifetime medical costs is $68 300 to $101 500/person. Hence, the cost per life-year gained is estimated at $24 500 to $50 700 ($34 000 to $70 200/QALY gained). Consistent with these results, the Sudden Cardiac Death in Heart Failure Trial economic analysis estimated an incremental cost of prophylactic ICD therapy at $33 200/life-year saved (1). Considering the eligibility criteria in these trials, 1 million Americans are potentially eligible for prophylactic ICD therapy.
Dialysis has been the acceptable standard for cost-effectiveness, now estimated at $120 000/QALY (2). In 2005 dollars, the cost-effectiveness of coronary artery bypass graft for 2-vessel coronary disease involving the left anterior descending artery with severe angina is $69 000/QALY (3). Thus, compared with many standard and accepted treatments, prophylactic ICD therapy is cost-effective. Given resource constraints, we will undoubtedly have to target or ration this therapy to as-yet-undefined subgroups at particularly high risk for sudden death with an overall medical prognosis and functional status that will allow them to reap the greatest benefit. Outpatient implantation of current or future devices that do not require a transvenous lead will further reduce implant cost. Device manufacturer exposure to product liability claims threatens any prospect for lower-cost devices in the United States. We should pay for life-saving prophylactic ICD therapy. The question remains whether our society can afford it.
Design: Analysis of the National Registry of Myocardial Infarction database (April 1998 to October 2002).
Description of prediction guide: The TRI was derived from 12 353 patients with STEMI and was calculated using the equation: TRI = heart rate × (age ÷ 10)2÷ systolic pressure (TRI values began with 0, and 10-point intervals were used). The TRI categorized patients into 3 risk groups: high risk = score > 60, intermediate risk = score 30 to 60, and low risk = score 0 to 29.
The TRI had good discriminative capacity to predict in-hospital mortality in patients with NSTEMI (c statistic = 0.73). Overall mortality in patients with NSTEMI (10.9%) was higher than that in patients registered in the same database with STEMI treated with reperfusion therapy (6.6%), but lower than that in patients with STEMI not treated with reperfusion therapy (18.7%). Rates of in-hospital mortality by TRI scores are in the Table.
*Percentage of patients and in-hospital mortality provided by author; +LR and CI defined in Glossary and calculated from percentage of patients and in-hospital mortality.
Risk prediction rules are useful to clinicians if they: 1) have been validated in unselected patients rather than clinical trial participants in whom rules are often derived with overestimated values; 2) require a small number of readily accessible and reliable clinical variables; 3) can be easily calculated and applied at the bedside; 4) present reasonable predictive accuracy; and 5) have been shown to enhance quality of decision making and patient outcomes by identifying higher-risk patients to whom therapeutic interventions can be aggressively targeted. The study by Wiviott and colleagues showed that the TRI seemed to satisfy the first 4 of these criteria in predicting in-hospital mortality in patients with MI, although its predictive accuracy was lower for NSTEMI patients (c statistic = 0.73) than for STEMI patients (c statistic = 0.79) and was highest for STEMI patients receiving reperfusion therapy (c statistic = 0.81) (1). Whether the rule is as useful as other recently validated rules for predicting longer-term mortality in patients who survive to discharge (2) remains to be determined. Satisfying the fifth criteria is the next challenge.
Studies showing underuse of effective therapies in high-risk patients (3) suggest the need for simple tools that help clinicians identify patients who have the most to gain from these therapies. Costly and potentially harmful treatments, including antithrombotic agents and percutaneous coronary intervention, are being used in patients with NSTEMI. Thus, a controlled trial in which routine use of the TRI is compared with usual decision making in decreasing risk-intervention mismatch and patient harm is warranted.