Cost-effectiveness of diagnostic strategies for venous thromboembolism: a systematic review

To support patients and health professionals in venous thromboembolism (VTE) diagnosis, the American Society of Hematology (ASH) together with the MacGRADE center at McMaster University developed evidence-based guidelines on diagnostic strategies for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE.¹  Various strategies including d-dimer testing, ultrasound, computed tomography pulmonary angiogram (CTPA), and ventilation-perfusion scan (V/Q scan) used alone and in various combinations in the diagnostic evaluation for a first and recurrent suspected VTE were used. Accurate diagnosis of VTE is important because of the morbidity and mortality associated with missed diagnoses and the potential side effects and/or inconvenience, and resource implications of diagnosis and anticoagulant treatment given for VTE.¹  Thus, following the Evidence to Decision frameworks,^2,3  the guideline recommendations were calibrated based on economic evidence, to consider the value for money and the impact on the budget of the alternative strategies to diagnose VTE.

Cost-effectiveness analysis or cost-utility analysis compares the relative costs and outcomes of different strategies and helps health care researchers determine the value for money of the strategies of interest. In other words, it assesses whether the additional benefit in outcomes is worth the additional cost. For guideline developers, considering cost-effectiveness evidence in decision making means answering questions about value for money, which means a holistic consideration of the net clinical benefit, uncertainty in evidence about the clinical benefit, and uncertainty in how much people value the clinical benefit.^2-4  Meanwhile, it is also critical to consider the affordability, that is, resource implications of recommended strategies. Budget impact analysis is an economic analysis that estimates the financial consequences of adopting an intervention.⁵  The consideration of value for money and resource implications in the guideline development process can be informed either by formal economic evaluations (eg, cost-effectiveness or cost-utility analysis, budget impact analysis), or by systematic reviews of existing economic evaluations.⁶  Systematic reviews of economic evaluations has gained popularity in recent years.^7-9  Systematically summarizing and critically appraising health economic evidence facilitates the development of transparent and cost-conscious guideline recommendations. Specific to the scope of the guidelines, there have been cost-effectiveness analyses on the diagnostic strategies for VTE, but systematic reviews which provide a detailed overview of relevant evidence are lacking. To inform the guideline on the diagnosis of VTE, we conducted a systematic review focused on the cost-effectiveness of diagnostic strategies for VTE within the guideline scope, which mainly considered d-dimer and ultrasound for DVT, and d-dimer, V/Q scan, and CTPA for PE.

Because the systematic review findings might help inform a wider audience than guideline developers, we updated the evidence to March 2021 for the purposes of this publication. This systematic review aims to assess the cost-effectiveness or budget impact of all diagnostic strategies for VTE.

We systematically searched, summarized, and critically appraised the economic evidence on diagnostic strategies for VTE. We reported this review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹⁰ 

To comprehensively search relevant records, we performed an economic literature search on 12 December 2016 to retrieve studies published from Medline (Ovid) and Embase (Ovid) until the search date. We created an auto search alert to update the search results until March 2021. To retrieve health economics-relevant studies, we applied an economic and costing filter developed by the Scottish Intercollegiate Guidelines Network.¹¹  We also performed a targeted gray literature search on the National Health Service Economic Evaluation Database and the Cost-Effectiveness Analysis Registry (see supplemental Document 1 for search strategies).

We screened the retrieved records with the prespecified inclusion and exclusion criteria. Primary studies were eligible if they met the following inclusion criteria: included a population of adults (18 years and older) undergoing diagnostic or screening tests for DVT, PE, recurrent DVT, or recurrent PE (includes any type of patient, adult with no risk factors, adult with known risk factors such as pregnancy, cancer, thrombophilia), evaluated a diagnostic or screening tests for VTE. Outcomes of interest included: cost-effectiveness analysis, cost-utility analysis, or cost-benefit analysis of VTE diagnostic strategies; cost comparisons of VTE diagnostic or screening strategies; health care service utilization comparisons of VTE diagnostic or screening strategies; and budget impact analyses. We excluded the following information: nonoriginal report (eg, review, commentary, communication); conference abstracts and structured abstracts; project record; letter/commentary; and case reports. We set no restriction on the publication language or year.

We managed citations through Endnote and conducted a duplicate initial screening of titles and abstracts by 2 independent reviewers. We then obtained the full text of studies that appeared eligible for review according to the inclusion criteria by either reviewer. We examined the full-text articles and selected studies eligible for inclusion. Two independent reviewers conducted the full-text review in duplicate and resolved the disagreement through consensus discussion. If necessary, a third reviewer was consulted. The reviewer also examined reference lists for any additional relevant studies from the guideline’s other systematic reviews.

We extracted relevant data on study characteristics and health economic outcomes, including the following details: source (eg, citation information, study type), methods (eg, study design, perspective, time horizon, population, intervention[s], comparator[s]), and outcomes (eg, health outcomes, costs, incremental cost-effectiveness ratios, sensitivity analyses).

For model-based cost-effectiveness or cost-utility analyses, we determined the study quality of each identified study by applying a modified quality appraisal checklist.¹²  We did not assess the study limitations for studies only on cost comparison or budget impact analysis. We did not conduct body of evidence level quality assessment.

The economic literature search yielded 834 citations published until 7 March 2021, after removing duplicates. We identified 49 studies that met our inclusion criteria (see supplemental Document 2 for reference list of included studies). Figure 1 shows the PRISMA flow diagram for the literature search and screening process.

Tables 1 and 2 summarize the characteristics of included studies. Of all the included reports, 21 were from North America (including 16 from the United States, and 5 from Canada), 24 from Europe (including 10 from the Netherlands, 4 from Switzerland, 3 from the United Kingdom, 2 from France and Spain, and 1 each from Italy, Serbia, and Sweden), and 1 each from Argentina, Australia, and Thailand. One further study was reported by researchers from multiple countries without specifying which country the results apply to. Twenty-six economic evaluations assessed the diagnosis of PE, 24 the diagnosis of DVT (with 1 on both).

In total, 37 studies used decision analysis or decision analytic model strategy to assess the cost-effectiveness of alternative strategies. Of these 37 reports, 34 considered both diagnosis and treatment-related costs, but 3 reports considered only diagnosis related costs. However, only 10 of these 37 reports considered a time frame longer than 1 year, so for most of the analyses neither costs nor health outcomes were discounted because of the short time horizon. Only 10 studies used cost per quality adjusted life-year as the indication of cost-effectiveness. Although 2 studies used diagnostic accuracy as the outcome, the other studies used diagnostic accuracy information as the model inputs. As for the trustworthiness of clinical evidence, only 8 studies were based on systematic reviews or meta-analyses, and 20 studies based on “literature review” or “literature.” Table 3 summarizes the study limitation of model-based analyses.

Table 1 summarizes the economic evaluations of diagnosis and screening for PE. Of these studies, 6 did not report the prevalence of PE (pretest probability unknown) and studied the cost-effectiveness among an unselected population. Most of the remaining studies were on patients with intermediate risk of PE, except 1 that evaluated a low-risk population (prevalence of 5%),¹³  and 1 considered a subgroup of a high-risk population (prevalence of 69%).¹⁴ 

Several cost-effectiveness analyses compared the diagnostic strategies with d-dimer and use of CTPA according to the d-dimer result with other strategies, including no diagnostic testing, or anticoagulant treatment of all patients with suspected PE, or universal CTPA or V/Q scan. In general, the strategy to combine d-dimer with another expensive strategy was suggested to be cost-effective or cost-saving.^14-25 

Cost-effectiveness analyses compared V/Q scan with other diagnosis strategies. None of the reports suggested V/Q scan was cost-effective compared with CTPA.^13,23,26,27  Another report suggested V/Q scan was cost-effective compared with CT alone,²⁸  with 20.1 additional lives saved per 1000 patients, at a cost of $940 per life-year gained. No evidence on the cost-effectiveness of single-photon emission CT was identified. Other reports suggested that the use of V/Q scan according to the ultrasound or d-dimer results could be cost-effective or cost saving.^14-20,29,30 

The included studies on the cost-effectiveness of CTPA varied in regard to the compared strategy, the setting, the time frame, and the analysis methods. In general, the CTPA strategy was considered effective, mostly associated with improved survival. However, the cost-effectiveness of CTPA was inconclusive.

Batalles et al²⁶  concluded that CTPA was cost-effective compared with pulmonary magnetic resonance imaging (MRI), and was the most effective strategy. A study by van Erkel et al²³  found that CTPA reduced mortality and improves cost-effectiveness in the diagnostic workup of suspected PE when compared with other strategies involving combinations of V/Q, ultrasound, d-dimer, and conventional angiography strategies. In Oudkerk,³¹  the “treatment for all” strategy had the lowest mortality but highest cost. Compared with this treatment for all strategy, pulmonary angiography strategies with or without prior V/Q lung scintigraphy and ultrasound of the legs had comparable low mortality, but also saved costs by ∼40%, and led to inappropriate treatment in fewer than 5% of patients. Paterson et al²⁷  found higher costs for CTPA as the initial diagnostic test but with improved expected survival when compared with a gradual algorithm of V/Q scanning followed by compression ultrasound and CTPA.

Doyle et al¹³  conducted a study in the United States that included a decision analytic model on diagnostic tests of PE in women to determine which strategy is the most cost-effective with the least number of deaths from PE. Of the strategies compared (ultrasound, V/Q scan, and spiral CT), spiral CT as the initial diagnostic regimen was found to be the most cost-effective at $17 208 per life saved (2004). Other studies concluded CTPA was not cost-effective compared with ultrasound,³²  or compared with single-photon emission CT³³  but some reports suggested that the use of CTPA based on ultrasound or d-dimer results could be cost-effective or cost saving.^{14,19-22,29,30,34} 

Table 2 summarizes the economic evaluations of diagnosis and screening for DVT. Of these studies, 13 did not report the prevalence of DVT (pretest probability unknown) and studied the cost-effectiveness among an unselected population. Most of the remaining studies were on patients with intermediate risk of DVT, except 2 studies included a low-risk population (prevalence no higher than 10%) and a high-risk population (prevalence of 50% or higher).^35,36 

We identified reports on the cost-effectiveness of pretest probability combined with d-dimer testing and ultrasound. For all the included studies, d-dimer, followed by ultrasound is either cost-effective or cost saving.^35,37-42  We were unable to identify studies comparing the whole leg ultrasound vs proximal compression ultrasound after d-dimer testing.

One health technology assessment³⁹  report compared 31 strategies including pretest probability assessment using the Wells’ score, d-dimer, ultrasound, compared with a “no testing, no treatment” alternative. The optimal strategy for DVT diagnosis is to use ultrasound selectively in patients with a high clinical pretest probability or positive d-dimer. Radiological testing for all patients does not appear to be a cost-effective use of health service resources.

Hull et al⁴³  reported a cost-effectiveness analysis derived from a prospective study. The researchers concluded that compared with clinical diagnosis, outpatient diagnosis using noninvasive testing was the most cost-effective strategy. Serial Doppler ultrasound is more costly than serial impedance plethysmography. Combined Doppler ultrasound and serial impedance plethysmography offers a less costly strategy than serial ultrasound alone.

We identified 1 model-based cost-effectiveness analysis on the diagnosis of recurrent ipsilateral DVT.⁴⁴  This analysis compared different diagnostic strategies including a clinical decision rule, d-dimer test, compression ultrasound, and magnetic resonance direct thrombus imaging (MRDTI). The analysis was based on a prospective cohort with 234 patients and the prevalence of recurrent DVT was 43%. According to this analysis, strategies with MRDTI for suspected recurrent ipsilateral DVT decreased 1-year health care costs compared with strategies without MRDTI, with similar impact on mortality. However, this analysis did not consider the long-term impact on the costs and outcomes.⁴⁴ 

We identified some studies that were not directly relevant to our guideline questions but were about diagnosis and screening of VTE, for example, clinical probability algorithms⁴⁵  or different cutoff values^46,47  or types of d-dimer tests.⁴⁸ 

This systematic review summarizes the economic evaluation evidence for VTE diagnosis until March 2021. For PE, diagnostic strategies including d-dimer to exclude PE were cost-effective compared with strategies without d-dimer testing. Strategies with CTPA alone were associated with improved survival, but not necessarily cost-effective when compared with combination strategies including d-dimer testing. The cost-effectiveness of CTPA in relation to V/Q scan was inconclusive, but CTPA or V/Q scan following ultrasound or d-dimer results could be cost-effective or even cost saving. For DVT, strategies with d-dimer and/or ultrasound were cost-effective. These results on d-dimer test supported the ASH clinical practice guideline recommendation that for patients at low (unlikely) VTE risk, using d-dimer as the initial test reduces the need for diagnostic imaging. Our systematic review also supported the recommendations of V/Q scans and CTPA for PE diagnosis and ultrasound for DVT diagnosis. Notably, for both PE and DVT, most of the included studies assessed the cost-effectiveness in unselected populations, and the prevalence of VTE and pretest probability of the population is unknown.

Although most of the studies considered clinical outcomes rather than diagnostic accuracy outcomes only, our confidence in the systematic review results is limited by a short follow-up duration of shorter than a year (3 months in most studies). An appropriate time horizon in the economic evaluation needs to be long enough to notice a difference between strategies of interest and 3 months may be insufficient.

Furthermore, all except 1 of the economic evaluations considering sequential testing strategies identified in the systematic review assumed the performance independency of tests. However, it is highly likely when multiple tests are used for diagnosis, the tests will not perform independently. For example, in a sequential combination of 2 tests, the performance of the second test may differ depending on the results of the first test. Failing to account for this performance independency may lead to biased estimates for diagnostic accuracy outcomes, which will eventually lead to biased cost-effectiveness results.⁴¹  Another issue arising from complex sequential testing strategies is that each one of the research questions in the guideline considered 1 specific diagnostic test, but the economic evidence might have assessed diagnostic tests in a sequential testing strategy. This mismatch between the research questions and the available evidence further compromised our confidence in the systematic review results to provide high-quality economic evidence to support the guideline recommendation.

Strengths of our systematic review include that this is a comprehensive systematic review to summarize available economic evidence on the diagnosis of VTE. The scope of this systematic review is broad, and not limited to the scope of the guideline recommendations.

Nevertheless, we were limited in that we could not provide economic evidence stratified by pretest probability of VTE. We only identified limited economic evidence on diagnosis of recurrent VTE. Our systematic review was also limited by study limitations of included studies, for example, the follow-up and low quality of model inputs. The follow-up was limited as most of the included studies had a short follow-up duration. Moreover, though false-negative cases could be detected, these studies were inadequate in following up with individuals with false-positive results. Only a few of the included studies used systematic reviews as the basis for model input. Clinical evidence based on unsystematic methods is less trustworthy. Furthermore, we did not assess the quality of evidence in economic evaluations because of a lack of guidance on this topic. The findings should be interpreted with caution, given the limits of the methodology in this field.

Our systematic review also revealed a mismatch between what is needed and what is available in cost-effectiveness evidence. None of the included studies considered the cost-effectiveness of diagnostic strategies stratified by pretest probabilities of VTE and there is a lack of evidence on the diagnosis of recurrent VTE. Further studies on these questions are warranted. The methodology on systematic review of economic evidence has yet to be developed and future Grading of Recommendations Assessment, Development, and Evaluation endeavors are necessary to provide guidance on how to assess quality of evidence on model-based cost-effectiveness analyses and how to use the information, especially when there may be more than 1 study and quantitively pooling may not be feasible.⁴⁹ 

Our systematic review supported the recommendations on the diagnosis of VTE made by ASH, including recommendations of starting with d-dimer for assessment of patients at low pretest probability of VTE, and recommendations of V/Q scans and CTPA for PE diagnosis and ultrasound for DVT diagnosis.¹  Together with the guideline recommendations, our systematic review may facilitate the adoption of timely and cost-effective diagnostic testing for patients suspected of VTE. Moreover, there could be cost savings or offset by avoiding unnecessary diagnostic imaging.

Through systematic review, we summarized economic evidence on the diagnosis and screening of VTE to support the ASH guidelines for the diagnosis of VTE.

This systematic review was conducted to support the development of the American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism.

The entire guideline development process was funded by the American Society of Hematology. Through the McMaster GRADE Center, some researchers received salary (W.W. and H.B.) or grant support (R.A.M. and H.J.S.), and others participated to fulfill requirements of an academic degree or program or volunteered their time.

Contribution: Y.Z. and H.J.S. designed the study; Y.Z., H.A.B., H.G., I.E.-I., G.P.M., R.K., R.N., C.D., and W.W. screened the literature and/or abstracted the data; Y.Z. and H.A.B. drafted the manuscript; H.J.S., W.W., and R.N. coordinated the overall project; H.J.S. is cochair of the GRADE working group and was the principal investigator for this project; W.W., W.L., R.A.M., and H.J.S. contributed to the interpretation of the results and critical revision of the report; and all authors read and approved the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Yuan Zhang, Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4K1; e-mail: zhang243@mcmaster.ca.