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Cost-effective diagnostic Algorithms in pulmonary embolism: An updated analysis
Cost-effective Diagnostic Algorithms in Pulmonary Embolism: An Updated Analysis Arian R. van Erkel, MD, Peter M. T. Pattynama, MD
The development of a cost-effective algorithm for the diagnosis of pulmonary embolism (PE) is a significant challenge. PE affects an estimated 120,000 patients per year in the United States (1), and accurate diagnosis is mandatory to guide optimal treatment. The design of a cost-effective diagnostic algorithm is a complicated task, involving the combination of multiple diagnostic tests, each with its own merits and disadvantages, into a single diagnostic strategy. To assess the cost-effectiveness of such a strategy, a number of elements have to be taken into account, principally (a) resulting overall sensitivity, specificity, and mortality, (b) mortality rates for treated and untreated patients, and (c) the costs of diagnosis and treatment. In order to arrive at an optimized diagnostic algorithm for PE, we recently performed a cost-effectiveness analysis (CEA) based on a decision model (2). The CEA strongly suggested a prominent role for helical computed tomography (CT) of the pulmonary arteries, preceded by ultrasound for deep venous thrombosis (DVT) and/or the D-dimer assay to detect fibrinogen degradation products in the blood. Diagnostic strategies that included these three elements demonstrated optimal survival and/or cost-effectiveness, expressed as costs per life saved. This CEA received quite a favorable response from the
Acad Radiol 1998; 5(suppl 2):$321-$327 From Leiden University Medical Center, Bldg 1-C2s, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Address reprint requests to A.R,V.E. ©AUR, 1998
medical community, but some justified criticisms were also raised. In particular, three of the premises on which the CEA was based have been questioned, including the probability of DVT in patients with PE, the accuracy of the D-dimer test, and the mortality of untreated PE. Since publication of the original CEA, new patient series have appeared providing information on the probability of DVT coexisting with PE. These studies suggest that the actual probability is approximately 46%, considerably lower than the 65% previously assumed. More extensive data have also appeared on the accuracy of the D-dimer assays. Importantly, the accuracy of D-dimer assays in patients with comorbidity appears lower than assumed in the original CEA. In particular, comorbidity is associated with decreased specificity, and false-positive D-dimer test results were found to occur in more than 90% of these patients (3-5). Another assumption that was challenged was the mortality associated with withholding treatment for PE. In the original CEA, we assumed, based on an authoritative review article, that the mortality rate was 25% (6). Recently, however, this same author reasonably argued that although unknown, the mortality of untreated PE is probably much lower than 25% (7). Since any one of these factors in itself might influence the results of the CEA, we decided to reexamine the CEA to determine whether recommendations for an optimally cost-effective diagnostic strategy should be adjusted in the light of the updated information.
The criticisms listed above were addressed by making the following major adjustments to the original CEA. The baseline value for the probability of DVT in case of PE was recalculated as 46%, based on more recent literature data (see baseline values).
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Table 1 Strategies and Baseline Results No Comorbidity
CT strategies 1. CT 2. US and CT 3. P-scan and CT 4. P-scan, US and CT 5. US, P-scan, and CT 6. V/P-scan, US and CT PA strategies 7. US and PA 8. V/P-scan, US and PA D-dimer/CT strategies 9. D-dimer and CT 10. D-dimer, US, and CT 11. D-dimer, P-scan, and CT 12. D-dimer, P-scan, US, and CT 13. D-dimer, US, P-scan, and CT 14. D-dimer, V/P-scan, US, and CT D-dimer/PA strategies 15. D-dimer, US, and PA 16, D-dimer, V/P-scan, US and PA Reference strategies 17. Notherapy 18. All therapy
Comorbidity
Average Total Cost per Patient ($)
Survival (%)
Average Total Cost per Patient ($)
Survival (%)
1,(]38 1,125 1,092 1,163 1,173 1,456
99.30 99.39 99.19 99.28 99.83 99.34
Idem Idem Idem Idern Idem ldem
Idem Idem Idem dem Idem Idem
1,444 1,250
99.02 99.05
Idem Idem
Idem Idem
856 893 760 790 838 943
99.10 99.19 98.08 98.15 98.55 98.15
1,044 1,125 964 1,028 1,087 1,309
99.30 99.39 98.24 98.31 98.73 98.30
1,052 1,067
99.05 98.04
1,424 1,542
99.06 98.04
... 2,860
93.99 98.96
Idem Idem
Idem Idem
The accuracy of the D-dimer assay also was recalculated by including more data. Because the accuracy of the D-dimer test differs between patients with and without comorbidity, the CEA was performed for each of these subgroups separately. To fully investigate the clinical potential of the D-dimer assay, we added more diagnostic strategies using this test. The influence of the mortality of untreated PE was tested by means of sensitivity analysis.
Cost-effectiveness M o d e l The diagnostic strategies were implemented as branches of a decision tree using the DATA software package as has been described in the literature (2,8). The model simulates alternative diagnostic strategies for suspected PE while accounting for the baseline variables listed in Table 2. Two outcome parameters were assessed: expected survival at 3 months as a measure of effectiveness and the average realistic costs of diagnosis and therapy for PE.
Diagnostic Strategies From the original CEA, we selected the top seven helical CT and top two pulmonary angiography strategies. Other strategies were added that were otherwise identical but were preceded by the D-dimer test. In all, 16 realistic diagnostic strategies for PE were analyzed (Table 1 ). To put the possible outcomes of these strategies into perspective, two reference strategies were analyzed: no treatment in any patient and anticoagulant treatment in every patient. The assumptions underlying the diagnostic strategies are listed in the Appendix.
Baseline Values Baseline values are summarized in Table 2. The data on the probability of DVT in patients with proved PE was updated from the previous CEA. Based on information pooled from seven studies, 193 patients with pulmonary angiography-proved PE had, if corrected for the sensitivity of impedance plethysmography and ultrasound, a prevalence of DVT of 46% (range, 12.5-87.5) (9-15). Studies reporting DVT in patients suspected of having PE (ie, unproved PE) were excluded from the analysis.
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Table 2 Baseline Values for Variables Used in the Analysis Variable Prior probabilities Probability of PE Probability of coexisting DVT Probability of DVT in p a t i e n t s w i t h o u t PE Diagnostic a c c u r a c y Sensitivity PA Specificity PA Sensitivity helical CT Specificity helical CT Sensitivity US for DVT Specificity US for DVT Sensitivity D-dimer Patients with n o c o m o r b i d i t y Patients with c o m o r b i d i t y Specificity D - d i m e r Patients with n o c o m o r b i d i t y Patients with c o m o r b i d i t y Probability in c a s e of PE Normal perfusion scan N o n d i a g n o s t i c V/P scan High p r o b a b i l i t y V/P scan Probability in c a s e of n o PE Normal perfusion scan N o n - d i a g n o s t i c V/P scan High p r o b a b i l i t y V/P scan Complications Mortality PA Mortality helical CT Costs in U.S.$ PA Helical CT US D-dimer Perfusion scan Ventilation scan Anticoagulant treatment Prognosis Mortality t r e a t e d PE Mortality u n t r e a t e d PE Fatal PE in p a t i e n t s with t r e a t e d DVT Fatal PE in p a t i e n t s with u n t r e a t e d DVT Mortality h e p a r i n t r e a t m e n t (5-10 days) Mortality c o u m a r i n t r e a t m e n t (3 m o n t h s )
Baseline V a l u e
Range
24% 46% 0.1%
19.9 - 32.2 12.5 - 87.5
98% 97% 95.5% 97.6% 80% 99%
95.7 - 99.0 63.6 88.9 66.1 95.9
-
100 100 85.0 100
96.1% 100%
83.3 - 100
60.4% 7.7%
42.1 - 97.6 2.8 - 20.7
2% 57% 41% 20% 78% 2% 0.5% 0.001% 660 330 85 30 130 330 2860 1% 25% 0.2% 11% 0.5% 0.3%
The accuracy of the D-dimer assay was calculated from three studies (387 patients) reporting accuracy for patients both with and without comorbidity (3-5). In all studies, comorbidity was defined as recent trauma, surgery, myocardial infarction or stroke, acute infection, disseminated intravascular coagulation, pregnancy or recent delivery, active collagen vascular disease, or metastatic cancer.
0 - 2.6 0 - 1.9 0 - 0.7 0 - 0.6
All other baseline values remained the same as in the original CEA and were based on the pooled data of peerreviewed publications retrieved through systematic MEDLINE searches and additional searches of the bibliographies of the thus found publications. The cost analysis was performed from the perspective of the hospital by combining costs for equipment, medical materials, and
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Patients without comorbidity
Patients with comorbidity
1200
1200
/
1100 1000 900 o
co
f
1100 1000
to
900
8
g 800
800
70O
i
98
100
9'9 Survival (%)
7OO 98
i
I
99
100
Survival (%)
O CT El US/CT • DD/CT • DDIUSIPICT I -k DD/USICT • DD/P/US/CT • DD/PICT
I
I o CT D US/CT DDIUS/CT • DD/p/us/CT
• DD/CT • DDIP/CT
]
Figure I.
Cost-effectiveness graph for patients without comorbidity. Survival is on the horizontal axis a n d costs are on the vertical axis. Only strategies that are not e x c l u d e d by absolute d o m i n a n c e are d e p i c t e d . The lines represent the incremental cost-effectiveness. Strategies that are a b o v e these lines are e x c l u d e d by e x t e n d e d d o m i n a n c e . Incremental cost-effectiveness is provided in Table 3.
Figure 2. Cost-effectiveness graph for patients with comorbidity. Survival is on the horizontal axis a n d costs are on the vertical axis. Only strategies that are not e x c l u d e d by absolute d o m i n a n c e are d e p i c t e d . The lines represent the incremental cost-effectiveness. Strategies that are a b o v e these lines are e x c l u d e d by e x t e n d e d d o m i n a n c e . Incremental cost-effectiveness is p r o v i d e d in Table 4.
personnel. A detailed explanation of basis for these decisions is provided in the original report (2).
sumed a maximum willingness to pay of $500,000 per life saved for patients without comorbidity (17,18). For patients with comorbidity we assumed an average life expectancy of 10 years and a willingness to pay $200,000 per life saved. No attempt was made to account for the quality of life. These cutoff values are, of course, arbitrary and may vary since they depend on economic and political changes.
Sensitivity Analysis No reliable literature data are available on the mortality of untreated PE (7). To investigate the influence of this parameter we performed threshold sensitivity analyses (0%-25%) for patients with and without comorbidity. Sensitivity analysis is an instrument of decision analysis used to investigate the influence of changing a variable on the final results and conclusions of the analysis. Threshold sensitivity analysis determines the value of the variable at which the optimal strategy becomes equally (cost-) effective as another strategy.
Interpretation of Results Preference for strategies was based on cost-effectiveness principles. A diagnostic strategy was discarded by absolute dominance whenever a competing strategy yielded higher effectiveness at lower costs. A strategy leading to higher effectiveness at higher costs was compared to the next best strategy by incremental marginal cost-effectiveness (costs per extra life saved). In general, an incremental cost-effectiveness ratio below $20,000 (U.S. dollars) per additional quality-adjusted year of life saved is considered attractive (16). Based on the average age of patients (56.1 years) in the PIOPED study and the average life expectancy of people 55 years of age (25 years for individuals of both sexes and any race), we as-
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Using the CEA model we estimated the survival and average costs per patient for all the 16 diagnostic strategies, under baseline conditions for patients with and without comorbidity (Table 1). It-can be seen that strategies using helical CT have lower costs and higher survival than strategies that use pulmonary angiography. This confirms the results of the original CEA, which indicated that helical CT is more cost-effective than pulmonary angiography in diagnostic algorithms for PE. The results can also be graphically presented in a costeffectiveness graph, with survival on the horizontal axis and costs on the vertical axis (Figs 1, 2). For clarity, dominated strategies have been omitted. Comparison of patients without comorbidity with those with comorbidity demonstrates clearly that strategies including D-dimer tests are more costly in patients with comorbidity than in its absence. Obviously, comorbidity leads to less favorable cost-effectiveness of D-dimer strategies.
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DIAGNOSTIC ALGORITHMS IN PULMONARY EMBOLISM
Table 4 Marginal Cost-effectiveness: Patients with Comorbidity f
i
Costs per Extra Life Saved ($) 111 D-dimer, P-scan, and SCTA 12, D-dimer, P-scan, US, and SCTA 1, SCTA 9, D-dimer and SCTA 10. D-dimer, US, and SCTA 2, US and SCTA
. . 81,250 918 566,932 * *
.
.
.
. . . . . . . 6,98t (strat 11) . . . . 88,889 (strat 9) 88,889 (strat 9)
. . .
. .,. . 96,667 (strat 1) 96,667 (strat 1)
Note.--First column: c o m p a r e d to strategy mentioned directly above. Second and third column: c o m p a r e d to strategy between brackets. *Equal in both costs and survival.
Table 3 Marginal Cost-effectiveness: Patients with No Comorbidity
Sensitivity analysis for mortality of untreated PE Patients with no comorbidity
Costs per Extra Life Saved ($) 11. D-dimer, P-scan and SCTA 12. D-dimer, P-scan, US, and SCTA 13. D-dimer, US, P-scan, and SCTA 9. D-dimer and SCTA 10, D-dimer, US, and SCTA 1. SCTA 2. US and SCTA
0
5
.. • 41,429 12,250 3,273 41,111 131,818 96,667
16,596 (strat 11) 9,412 (strat 11)
The cost-effectiveness graph can also be used to compare the incremental marginal cost-effectiveness of a strategy with the next best strategy (by comparing the slope of the line connecting these data points (see Figs 1, 2). Points above these lines are strategies excluded by extended dominance (19). The exact incremental cost-effectiveness values of these strategies are provided in Table 3 for the group without comorbidity and in Table 4 for the patients with comorbidity. Assuming that society is willing to pay $500,000 for each additional life saved in the patient group without comorbidity, the most cost-effective strategy under baseline conditions is ultrasound followed by helical CT (US/CT). Using this strategy the average patient survival is 99.39% at an average cost of $1,125 per patient. The US/CT strategy has an incremental cost-effectiveness of $116,000 per extra life saved when compared with the best strategy previously recommended (ie, D-dimer/US/CT strategy, the same algorithm but preceded by the D-dimer test).
25
Figure 3. Sensitivity analysis for the effect of mortality of untreated PE on the cost-effectiveness of diagnostic strategies for patients without comorbidity (assuming a willingness to pay per extra life saved of $500,000). The most cost-effective strategies in the defined mortality ranges are indicated.
Sensitivity analysis for mortality of untreated PE Patients with comorbidity
116,000 (strat 10)
Note.--First column: c o m p a r e d to strategy mentioned directly above. Second column: c o m p a r e d to strategy between brackets.
10 15 20 I~Notherapy BIIDD/US/CTC3US/CT I
0
5
10 15 20 [R No therapy i C T DUS/CT 1
25
Figure 4. Sensitivity analysis for the effect of mortality of untreated PE on the cost-effectiveness of diagnostic strategies for patients with comorbidity (assuming a willingness to pay per extra life saved of $200,000). The most cost-effective strategies in the defined mortality ranges are indicated.
In patients with comorbidity, reduced life expectancy results in a lower willingness to pay ($200,000 per extra life saved, see above). Nevertheless, this does not result in a different recommended optimal strategy. Again, the US/CT strategy seems most cost-effective under baseline conditions. This strategy has an incremental cost-effectiveness of $96,667 per extra life saved when compared with the previous best strategy, which used helical CT only. Compared with the US/CT strategy, the D-dimer! US/CT strategy has identical survival at the same costs. Thus, adding the D-dimer test to the US/CT strategy is n o t rational, as this will not reduce costs or improve survival. Sensitivity analysis demonstrates that the optimal strategy is dependent on the mortality of untreated PE, but at
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relatively low values only. For patients without comorbidity (Fig 3), the US/CT strategy remains most cost-effective for a wide range of mortality values of untreated PE (from 8.3% to 25%). Below 8.3% mortality, the D-dimer/US/CT strategy is preferred. Below 2.6% mortality, the most costeffective strategy is not to treat. For patients with comorbidity (Fig 4) the results are similar but somewhat less stable. Between 12.5% and 25% mortality of untreated PE, the US/CT strategy is again the most cost-effective. Between 4.1% and 12.5% mortality, helical CT alone is the most cost-effective strategy. Below 4.1% mortality the no treatment strategy is most cost-effective. A strategy including D-dimer tests is not preferred for any mortality value between 0% and 25% of untreated PE.
A number of general conclusions can be drawn from this study. First, the present CEA confirms a prominent role for helical CT of the pulmonary arteries for the diagnosis of PE. After inclusion of the updated information on probability of DVT and on the accuracy of the D-dimer test, both in patients with and without comorbidity, strategies that include helical CT again proved more cost-effective than pulmonary angiography strategies. This conclusion proved to be valid for all assumed values of mortality of untreated PE higher than 2.8%. Of all diagnostic strategies under consideration, the US/ CT strategy seemed most cost-effective. This was the case both in patients with and without comorbidity and for a wide range of mortality of untreated PE, even with an assumption of lower probability of coexisting DVT. In the original CEA, we recommended the D-dimer/US/ helical CT strategy as most cost-effective. Contrary to these earlier findings, however, the updated CEA suggests that the use of the D-dimer test does not result in optimally cost-effective strategies. The newer patient series indicate that the accuracy of the D-dimer test for PE is less than previously assumed, and the D-dimer assay appears to limit the cost-effectiveness of strategies, especially in patients with comorbidity. Although a D-dimer strategy might be cost-effective in the group of patients with no comorbidity and a very low mortality of untreated PE (<8.3%), this was not the case in the comorbidity group. Comorbidity apparently leads to a less favorable cost-effectiveness of the D-dimer strategies. No strategy which included the D-dimer test was preferred at any mortality value of untreated PE from 0% to 25% in this group. The explanation, of course, is the reduced specificity of the D-
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dimer test, especially in comorbid states, resulting in many false-positive results and the need for additional testing. The influence of the mortality of untreated PE is another factor which needs to be considered. Generally it is assumed that the mortality of untreated PE is high, approximately 25%, based on a 1960 study by Barritt and Jordan (20). However, the mortality of untreated PE as reported in the various patient series may well depend on the severity of disease (7). Therefore, it has been argued that the high mortality reported by Barritt and Jordan was probably related to the method for diagnosis, which detected only severe PE (7,20). Nielsen et al (21) performed a nearplacebo controlled trial, treating half of the patients with PE with anticoagulant therapy and the other half with (ineffective) phenylbutazone 100 mg t.d.s. No deaths were encountered in the control group of 57 patients. In patients with PE after total hip replacement, Johnson and Charney (22) reported zero mortality in 308 untreated patients. In the latter two studies, all patients with clinically diagnosed PE were included in the data. Because the clinical diagnosis of PE is unreliable, an estimated three-quarters of these patients most probably did not have the disease (Table 2). Therefore, although the actual mortality rate for untreated PE is unknown, it is reasonable to assume that it is lower than 25%. In this respect, sensitivity analysis showed that the results of the CEA are stable and that the recommended optimal strategy should be reconsidered only at mortality values of less than 8% for patients without comorbidity and less than 12% for patients with comorbidity. In order to fully appreciate the CEA, it is necessary to understand the inherent limitations of the simplification of a decision model. By necessity, conditional independence of the diagnostic tests was assumed (Appendix). However, the sensitivity and specificity of a test may not be constant but rather depend on the results of a preceding test. Data on the accuracy of the various diagnostic tests are generally insufficient to control for this effect. Although life expectancy, especially if corrected for the quality of life, is the generally preferred outcome measure for cost-effectiveness analyses, patients with PE have a wide variety of severe comorbid conditions. Literature data are insufficient to make valid assumptions concerning the quality-adjusted life expectancy of these patients. In addition, costs and seriousness of complications, costs of dying, patient and physician satisfaction, availability and feasibility of diagnostic modalities, impact of a diagnostic modality on costs and duration of hospital stay, and implications of alternative diagnoses are all factors that may influence decisions in clinical practice.
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Using incremental marginal cost-effectiveness to determine the optimally cost-effective diagnostic strategy also has several limitations. Society's willingness to pay for an additional life saved is arbitrarily set and best used to compare different health-care programs. Using this parameter as a limit for the incremental cost-effectiveness of diagnostic strategies for an isolated clinical problem is in conflict with a health-care system with limited financial resources (23,24).
The results of the updated CEA reiterate a prominent role for helical CT in the diagnosis of PE. The D-dimer assay reduces the cost-effectiveness of diagnostic strategies for PE, especially in patients with comorbidity. Helical CT preceded by ultrasound (US/CT) appears to be the most cost-effective diagnostic strategy for PE. This is true both for patients with and without comorbidity and holds for a wide range of mortality values of untreated PE. The optimal strategy changes only at a low mortality value of untreated PE, which is, unfortunately, an unknown factor. Theoretic recommendations for an optimally cost-effective algorithm can therefore serve as best approximations only.
Assumptions on Diagnostic Strategies For all diagnostic strategies, the following basic principles were assumed: 1. Helical CT or pulmonary angiography serve as final tests to detect or exclude PE. 2. If DVT is detected by ultrasound, no further testing is considered necessary and anticoagulant therapy is initiated. Otherwise, the next diagnostic procedure in the algorithm will be performed. 3. The D-dimer test is used to exclude thromboembolic disease. If it is negative, no further diagnostic action is taken and no anticoagulant treatment is given. A positive D-dimer result prompts the next test in the algorithm. 4. Normal perfusion scintigraphy (P-scan) virtually excludes PE, and no additional testing is performed. The presence of perfusion defects prompts the next diagnostic procedure. 5. Ventilation scintigraphy (V-scan) is performed only after an abnormal P-scan. A high probability V/P-scan is taken as evidence of PE. All other V/P results are nondiagnostic and prompt the next test.
DIAGNOSTIC ALGORITHMS IN PULMONARY EMBOLISIV
6. The test results are treated according to Bayes' theorem, with the assumption that the sensitivity and specificity of the different diagnostic techniques are independent. !EFERENCE~ 1, Gillum RF. Pulmonary embolism and thrombophlebitis in the United States, 1970-1985, Am Heart J 1987; 114:1262-1264. 2, Van Erkel AR, Van Rossum AB, Bloem JL, Kievit J, Pattynama PMT. Spiral CT angiography for suspected pulmonary embolism: a cost-effectiveness analysis, Radiology 1996; 201:29-36. 3, Demers C, Ginsberg JS, Johnston M, Brill-gdwards P, Panju A. Ddimer and thrombin-antithrombin I1[ complexes in patients with clinically suspected pulmonary embolism. Thromb Haemost 1992; 67:408-412. 4. Ginsberg JS, BrilI-Edwards PA, Demers C, Donovan D, Panju A. Ddimer in patients with clinically suspected pulmonary embolism, Chest 1993; 104:1679-1684, 5, Ginsberg JS, Wells PS, BriiI-Edwards P, et al, Application of a novel and rapid whole blood assay for D-dimer in patients with clinically suspected pulmonary embolism, Thromb Haemost 1995; 73:35-38, 6, Egermayer P, Value of anticoagulants in the treatment of pulmonary embolism: a discussion paper, J R Soc Med 1981; 74:675681. 7, Egermayer P, Town GI, The clinical significance of pulmonary embolism: uncertainties and implications for treatment--a debate. J Intern Med 1997; 241:5-10. 8. TreeAge Software I, Decision analysis by TreeAge (DATA). Version 3.0.4. Computer program. 1996. 9, Hull RD, Hirsh J, Carter C J, et al. Diagnostic value of ventilationperfusion lung scanning in patients with suspected pulmonary embolism. Chest 1985; 88:819-828. 10, Schiff M J, Feinberg AW, Naidich JB, Noninvasive venous examinations as a screening test for pulmonary embolism, Arch Intern Med 1987; 147:505-507. 11, Killewich LA, Nunnelee JD, Auer AI. Value of lower extremity venous duplex examination in the diagnosis of pulmonary embolism, J Vasc Surg 1993; 17:934-939. 12, Quinn RJ, Nour R, Butler SP, et al. Pulmonary embolism in patients with intermediate probability lung scans: diagnosis with Doppler venous US and D-dimer measurement, Radiology 1994; 190:509511. 13, Smith LL, Iber C, Sirr S, Pulmonary embolism: confirmation with venous duplex US as adjunct to lung scanning. Radiology 1994; 191:143-147, 14, Christiansen F, Kellerth T, Ragnarsson A, Hjortevang F. Ultrasound at scintigraphic "intermediate probability of pulmonary embolism." Acta Radio11996; 37:14-17, 15, Turkstra F, Kuijer PMM, Van Beek EJR, Brandjes DPM, Ten Cate JW, Buller HR, Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism, Ann Intern Med 1997; 126:775-781. 16, Goldman L, Gordon DJ, Rifkind BM, et al. Cost and health implications of cholesterol lowering. Circulation 1992; 85:1960-1968, 17, The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990; 263:2753-2759. 18, Anderson RN, Kochanek KD, Murphy SL, Report of final mortality statistics 1995. Monthly Vital Statistics Report 1997; 45. 19. Hunink MGM, Review article: outcomes research and cost-effectiveness analysis in radiology, Eur Radio11996; 6:615-620, 20. Barritt DW, Jordan SC. Anticoagulant drugs in treatment of pulmonary embolism: a controlled trial. Lancet 1960; i:309-312, 21. Nielsen HK, Husted SE, Krusell LR, Charles P, Hansen HH. Silent pulmonary embolism in patients with d e e p venous thrombosis: incidence and fate in a randomized, controlled trial of anticoagulation versus no anticoagulation. J Intern Med 1994; 235:457-461. 22. Johnson R, Charney J. Treatment of pulmonary embolism in total hip replacement, Clin Ortop 1977; 124:149-154, 23. Eisenberg JM, A guide to the economic analysis of clinical practices. JAMA 1989; 262:2879-2886, 24. Black WC, The CE plane: a graphic representation of cost-effectiveness, Med Decis Making 1990; 10:212-214.
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The development of a cost-effective algorithm for the diagnosis of pulmonary embolism (PE) is a significant challenge. PE affects an estimated 120,000 patients per year in the United States (1), and accurate diagnosis is mandatory to guide optimal treatment. The design of a cost-effective diagnostic algorithm is a complicated task, involving the combination of multiple diagnostic tests, each with its own merits and disadvantages, into a single diagnostic strategy. To assess the cost-effectiveness of such a strategy, a number of elements have to be taken into account, principally (a) resulting overall sensitivity, specificity, and mortality, (b) mortality rates for treated and untreated patients, and (c) the costs of diagnosis and treatment. In order to arrive at an optimized diagnostic algorithm for PE, we recently performed a cost-effectiveness analysis (CEA) based on a decision model (2). The CEA strongly suggested a prominent role for helical computed tomography (CT) of the pulmonary arteries, preceded by ultrasound for deep venous thrombosis (DVT) and/or the D-dimer assay to detect fibrinogen degradation products in the blood. Diagnostic strategies that included these three elements demonstrated optimal survival and/or cost-effectiveness, expressed as costs per life saved. This CEA received quite a favorable response from the
Acad Radiol 1998; 5(suppl 2):$321-$327 From Leiden University Medical Center, Bldg 1-C2s, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Address reprint requests to A.R,V.E. ©AUR, 1998
medical community, but some justified criticisms were also raised. In particular, three of the premises on which the CEA was based have been questioned, including the probability of DVT in patients with PE, the accuracy of the D-dimer test, and the mortality of untreated PE. Since publication of the original CEA, new patient series have appeared providing information on the probability of DVT coexisting with PE. These studies suggest that the actual probability is approximately 46%, considerably lower than the 65% previously assumed. More extensive data have also appeared on the accuracy of the D-dimer assays. Importantly, the accuracy of D-dimer assays in patients with comorbidity appears lower than assumed in the original CEA. In particular, comorbidity is associated with decreased specificity, and false-positive D-dimer test results were found to occur in more than 90% of these patients (3-5). Another assumption that was challenged was the mortality associated with withholding treatment for PE. In the original CEA, we assumed, based on an authoritative review article, that the mortality rate was 25% (6). Recently, however, this same author reasonably argued that although unknown, the mortality of untreated PE is probably much lower than 25% (7). Since any one of these factors in itself might influence the results of the CEA, we decided to reexamine the CEA to determine whether recommendations for an optimally cost-effective diagnostic strategy should be adjusted in the light of the updated information.
The criticisms listed above were addressed by making the following major adjustments to the original CEA. The baseline value for the probability of DVT in case of PE was recalculated as 46%, based on more recent literature data (see baseline values).
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Table 1 Strategies and Baseline Results No Comorbidity
CT strategies 1. CT 2. US and CT 3. P-scan and CT 4. P-scan, US and CT 5. US, P-scan, and CT 6. V/P-scan, US and CT PA strategies 7. US and PA 8. V/P-scan, US and PA D-dimer/CT strategies 9. D-dimer and CT 10. D-dimer, US, and CT 11. D-dimer, P-scan, and CT 12. D-dimer, P-scan, US, and CT 13. D-dimer, US, P-scan, and CT 14. D-dimer, V/P-scan, US, and CT D-dimer/PA strategies 15. D-dimer, US, and PA 16, D-dimer, V/P-scan, US and PA Reference strategies 17. Notherapy 18. All therapy
Comorbidity
Average Total Cost per Patient ($)
Survival (%)
Average Total Cost per Patient ($)
Survival (%)
1,(]38 1,125 1,092 1,163 1,173 1,456
99.30 99.39 99.19 99.28 99.83 99.34
Idem Idem Idem Idern Idem ldem
Idem Idem Idem dem Idem Idem
1,444 1,250
99.02 99.05
Idem Idem
Idem Idem
856 893 760 790 838 943
99.10 99.19 98.08 98.15 98.55 98.15
1,044 1,125 964 1,028 1,087 1,309
99.30 99.39 98.24 98.31 98.73 98.30
1,052 1,067
99.05 98.04
1,424 1,542
99.06 98.04
... 2,860
93.99 98.96
Idem Idem
Idem Idem
The accuracy of the D-dimer assay also was recalculated by including more data. Because the accuracy of the D-dimer test differs between patients with and without comorbidity, the CEA was performed for each of these subgroups separately. To fully investigate the clinical potential of the D-dimer assay, we added more diagnostic strategies using this test. The influence of the mortality of untreated PE was tested by means of sensitivity analysis.
Cost-effectiveness M o d e l The diagnostic strategies were implemented as branches of a decision tree using the DATA software package as has been described in the literature (2,8). The model simulates alternative diagnostic strategies for suspected PE while accounting for the baseline variables listed in Table 2. Two outcome parameters were assessed: expected survival at 3 months as a measure of effectiveness and the average realistic costs of diagnosis and therapy for PE.
Diagnostic Strategies From the original CEA, we selected the top seven helical CT and top two pulmonary angiography strategies. Other strategies were added that were otherwise identical but were preceded by the D-dimer test. In all, 16 realistic diagnostic strategies for PE were analyzed (Table 1 ). To put the possible outcomes of these strategies into perspective, two reference strategies were analyzed: no treatment in any patient and anticoagulant treatment in every patient. The assumptions underlying the diagnostic strategies are listed in the Appendix.
Baseline Values Baseline values are summarized in Table 2. The data on the probability of DVT in patients with proved PE was updated from the previous CEA. Based on information pooled from seven studies, 193 patients with pulmonary angiography-proved PE had, if corrected for the sensitivity of impedance plethysmography and ultrasound, a prevalence of DVT of 46% (range, 12.5-87.5) (9-15). Studies reporting DVT in patients suspected of having PE (ie, unproved PE) were excluded from the analysis.
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Table 2 Baseline Values for Variables Used in the Analysis Variable Prior probabilities Probability of PE Probability of coexisting DVT Probability of DVT in p a t i e n t s w i t h o u t PE Diagnostic a c c u r a c y Sensitivity PA Specificity PA Sensitivity helical CT Specificity helical CT Sensitivity US for DVT Specificity US for DVT Sensitivity D-dimer Patients with n o c o m o r b i d i t y Patients with c o m o r b i d i t y Specificity D - d i m e r Patients with n o c o m o r b i d i t y Patients with c o m o r b i d i t y Probability in c a s e of PE Normal perfusion scan N o n d i a g n o s t i c V/P scan High p r o b a b i l i t y V/P scan Probability in c a s e of n o PE Normal perfusion scan N o n - d i a g n o s t i c V/P scan High p r o b a b i l i t y V/P scan Complications Mortality PA Mortality helical CT Costs in U.S.$ PA Helical CT US D-dimer Perfusion scan Ventilation scan Anticoagulant treatment Prognosis Mortality t r e a t e d PE Mortality u n t r e a t e d PE Fatal PE in p a t i e n t s with t r e a t e d DVT Fatal PE in p a t i e n t s with u n t r e a t e d DVT Mortality h e p a r i n t r e a t m e n t (5-10 days) Mortality c o u m a r i n t r e a t m e n t (3 m o n t h s )
Baseline V a l u e
Range
24% 46% 0.1%
19.9 - 32.2 12.5 - 87.5
98% 97% 95.5% 97.6% 80% 99%
95.7 - 99.0 63.6 88.9 66.1 95.9
-
100 100 85.0 100
96.1% 100%
83.3 - 100
60.4% 7.7%
42.1 - 97.6 2.8 - 20.7
2% 57% 41% 20% 78% 2% 0.5% 0.001% 660 330 85 30 130 330 2860 1% 25% 0.2% 11% 0.5% 0.3%
The accuracy of the D-dimer assay was calculated from three studies (387 patients) reporting accuracy for patients both with and without comorbidity (3-5). In all studies, comorbidity was defined as recent trauma, surgery, myocardial infarction or stroke, acute infection, disseminated intravascular coagulation, pregnancy or recent delivery, active collagen vascular disease, or metastatic cancer.
0 - 2.6 0 - 1.9 0 - 0.7 0 - 0.6
All other baseline values remained the same as in the original CEA and were based on the pooled data of peerreviewed publications retrieved through systematic MEDLINE searches and additional searches of the bibliographies of the thus found publications. The cost analysis was performed from the perspective of the hospital by combining costs for equipment, medical materials, and
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Patients without comorbidity
Patients with comorbidity
1200
1200
/
1100 1000 900 o
co
f
1100 1000
to
900
8
g 800
800
70O
i
98
100
9'9 Survival (%)
7OO 98
i
I
99
100
Survival (%)
O CT El US/CT • DD/CT • DDIUSIPICT I -k DD/USICT • DD/P/US/CT • DD/PICT
I
I o CT D US/CT DDIUS/CT • DD/p/us/CT
• DD/CT • DDIP/CT
]
Figure I.
Cost-effectiveness graph for patients without comorbidity. Survival is on the horizontal axis a n d costs are on the vertical axis. Only strategies that are not e x c l u d e d by absolute d o m i n a n c e are d e p i c t e d . The lines represent the incremental cost-effectiveness. Strategies that are a b o v e these lines are e x c l u d e d by e x t e n d e d d o m i n a n c e . Incremental cost-effectiveness is provided in Table 3.
Figure 2. Cost-effectiveness graph for patients with comorbidity. Survival is on the horizontal axis a n d costs are on the vertical axis. Only strategies that are not e x c l u d e d by absolute d o m i n a n c e are d e p i c t e d . The lines represent the incremental cost-effectiveness. Strategies that are a b o v e these lines are e x c l u d e d by e x t e n d e d d o m i n a n c e . Incremental cost-effectiveness is p r o v i d e d in Table 4.
personnel. A detailed explanation of basis for these decisions is provided in the original report (2).
sumed a maximum willingness to pay of $500,000 per life saved for patients without comorbidity (17,18). For patients with comorbidity we assumed an average life expectancy of 10 years and a willingness to pay $200,000 per life saved. No attempt was made to account for the quality of life. These cutoff values are, of course, arbitrary and may vary since they depend on economic and political changes.
Sensitivity Analysis No reliable literature data are available on the mortality of untreated PE (7). To investigate the influence of this parameter we performed threshold sensitivity analyses (0%-25%) for patients with and without comorbidity. Sensitivity analysis is an instrument of decision analysis used to investigate the influence of changing a variable on the final results and conclusions of the analysis. Threshold sensitivity analysis determines the value of the variable at which the optimal strategy becomes equally (cost-) effective as another strategy.
Interpretation of Results Preference for strategies was based on cost-effectiveness principles. A diagnostic strategy was discarded by absolute dominance whenever a competing strategy yielded higher effectiveness at lower costs. A strategy leading to higher effectiveness at higher costs was compared to the next best strategy by incremental marginal cost-effectiveness (costs per extra life saved). In general, an incremental cost-effectiveness ratio below $20,000 (U.S. dollars) per additional quality-adjusted year of life saved is considered attractive (16). Based on the average age of patients (56.1 years) in the PIOPED study and the average life expectancy of people 55 years of age (25 years for individuals of both sexes and any race), we as-
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Using the CEA model we estimated the survival and average costs per patient for all the 16 diagnostic strategies, under baseline conditions for patients with and without comorbidity (Table 1). It-can be seen that strategies using helical CT have lower costs and higher survival than strategies that use pulmonary angiography. This confirms the results of the original CEA, which indicated that helical CT is more cost-effective than pulmonary angiography in diagnostic algorithms for PE. The results can also be graphically presented in a costeffectiveness graph, with survival on the horizontal axis and costs on the vertical axis (Figs 1, 2). For clarity, dominated strategies have been omitted. Comparison of patients without comorbidity with those with comorbidity demonstrates clearly that strategies including D-dimer tests are more costly in patients with comorbidity than in its absence. Obviously, comorbidity leads to less favorable cost-effectiveness of D-dimer strategies.
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Table 4 Marginal Cost-effectiveness: Patients with Comorbidity f
i
Costs per Extra Life Saved ($) 111 D-dimer, P-scan, and SCTA 12, D-dimer, P-scan, US, and SCTA 1, SCTA 9, D-dimer and SCTA 10. D-dimer, US, and SCTA 2, US and SCTA
. . 81,250 918 566,932 * *
.
.
.
. . . . . . . 6,98t (strat 11) . . . . 88,889 (strat 9) 88,889 (strat 9)
. . .
. .,. . 96,667 (strat 1) 96,667 (strat 1)
Note.--First column: c o m p a r e d to strategy mentioned directly above. Second and third column: c o m p a r e d to strategy between brackets. *Equal in both costs and survival.
Table 3 Marginal Cost-effectiveness: Patients with No Comorbidity
Sensitivity analysis for mortality of untreated PE Patients with no comorbidity
Costs per Extra Life Saved ($) 11. D-dimer, P-scan and SCTA 12. D-dimer, P-scan, US, and SCTA 13. D-dimer, US, P-scan, and SCTA 9. D-dimer and SCTA 10, D-dimer, US, and SCTA 1. SCTA 2. US and SCTA
0
5
.. • 41,429 12,250 3,273 41,111 131,818 96,667
16,596 (strat 11) 9,412 (strat 11)
The cost-effectiveness graph can also be used to compare the incremental marginal cost-effectiveness of a strategy with the next best strategy (by comparing the slope of the line connecting these data points (see Figs 1, 2). Points above these lines are strategies excluded by extended dominance (19). The exact incremental cost-effectiveness values of these strategies are provided in Table 3 for the group without comorbidity and in Table 4 for the patients with comorbidity. Assuming that society is willing to pay $500,000 for each additional life saved in the patient group without comorbidity, the most cost-effective strategy under baseline conditions is ultrasound followed by helical CT (US/CT). Using this strategy the average patient survival is 99.39% at an average cost of $1,125 per patient. The US/CT strategy has an incremental cost-effectiveness of $116,000 per extra life saved when compared with the best strategy previously recommended (ie, D-dimer/US/CT strategy, the same algorithm but preceded by the D-dimer test).
25
Figure 3. Sensitivity analysis for the effect of mortality of untreated PE on the cost-effectiveness of diagnostic strategies for patients without comorbidity (assuming a willingness to pay per extra life saved of $500,000). The most cost-effective strategies in the defined mortality ranges are indicated.
Sensitivity analysis for mortality of untreated PE Patients with comorbidity
116,000 (strat 10)
Note.--First column: c o m p a r e d to strategy mentioned directly above. Second column: c o m p a r e d to strategy between brackets.
10 15 20 I~Notherapy BIIDD/US/CTC3US/CT I
0
5
10 15 20 [R No therapy i C T DUS/CT 1
25
Figure 4. Sensitivity analysis for the effect of mortality of untreated PE on the cost-effectiveness of diagnostic strategies for patients with comorbidity (assuming a willingness to pay per extra life saved of $200,000). The most cost-effective strategies in the defined mortality ranges are indicated.
In patients with comorbidity, reduced life expectancy results in a lower willingness to pay ($200,000 per extra life saved, see above). Nevertheless, this does not result in a different recommended optimal strategy. Again, the US/CT strategy seems most cost-effective under baseline conditions. This strategy has an incremental cost-effectiveness of $96,667 per extra life saved when compared with the previous best strategy, which used helical CT only. Compared with the US/CT strategy, the D-dimer! US/CT strategy has identical survival at the same costs. Thus, adding the D-dimer test to the US/CT strategy is n o t rational, as this will not reduce costs or improve survival. Sensitivity analysis demonstrates that the optimal strategy is dependent on the mortality of untreated PE, but at
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relatively low values only. For patients without comorbidity (Fig 3), the US/CT strategy remains most cost-effective for a wide range of mortality values of untreated PE (from 8.3% to 25%). Below 8.3% mortality, the D-dimer/US/CT strategy is preferred. Below 2.6% mortality, the most costeffective strategy is not to treat. For patients with comorbidity (Fig 4) the results are similar but somewhat less stable. Between 12.5% and 25% mortality of untreated PE, the US/CT strategy is again the most cost-effective. Between 4.1% and 12.5% mortality, helical CT alone is the most cost-effective strategy. Below 4.1% mortality the no treatment strategy is most cost-effective. A strategy including D-dimer tests is not preferred for any mortality value between 0% and 25% of untreated PE.
A number of general conclusions can be drawn from this study. First, the present CEA confirms a prominent role for helical CT of the pulmonary arteries for the diagnosis of PE. After inclusion of the updated information on probability of DVT and on the accuracy of the D-dimer test, both in patients with and without comorbidity, strategies that include helical CT again proved more cost-effective than pulmonary angiography strategies. This conclusion proved to be valid for all assumed values of mortality of untreated PE higher than 2.8%. Of all diagnostic strategies under consideration, the US/ CT strategy seemed most cost-effective. This was the case both in patients with and without comorbidity and for a wide range of mortality of untreated PE, even with an assumption of lower probability of coexisting DVT. In the original CEA, we recommended the D-dimer/US/ helical CT strategy as most cost-effective. Contrary to these earlier findings, however, the updated CEA suggests that the use of the D-dimer test does not result in optimally cost-effective strategies. The newer patient series indicate that the accuracy of the D-dimer test for PE is less than previously assumed, and the D-dimer assay appears to limit the cost-effectiveness of strategies, especially in patients with comorbidity. Although a D-dimer strategy might be cost-effective in the group of patients with no comorbidity and a very low mortality of untreated PE (<8.3%), this was not the case in the comorbidity group. Comorbidity apparently leads to a less favorable cost-effectiveness of the D-dimer strategies. No strategy which included the D-dimer test was preferred at any mortality value of untreated PE from 0% to 25% in this group. The explanation, of course, is the reduced specificity of the D-
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dimer test, especially in comorbid states, resulting in many false-positive results and the need for additional testing. The influence of the mortality of untreated PE is another factor which needs to be considered. Generally it is assumed that the mortality of untreated PE is high, approximately 25%, based on a 1960 study by Barritt and Jordan (20). However, the mortality of untreated PE as reported in the various patient series may well depend on the severity of disease (7). Therefore, it has been argued that the high mortality reported by Barritt and Jordan was probably related to the method for diagnosis, which detected only severe PE (7,20). Nielsen et al (21) performed a nearplacebo controlled trial, treating half of the patients with PE with anticoagulant therapy and the other half with (ineffective) phenylbutazone 100 mg t.d.s. No deaths were encountered in the control group of 57 patients. In patients with PE after total hip replacement, Johnson and Charney (22) reported zero mortality in 308 untreated patients. In the latter two studies, all patients with clinically diagnosed PE were included in the data. Because the clinical diagnosis of PE is unreliable, an estimated three-quarters of these patients most probably did not have the disease (Table 2). Therefore, although the actual mortality rate for untreated PE is unknown, it is reasonable to assume that it is lower than 25%. In this respect, sensitivity analysis showed that the results of the CEA are stable and that the recommended optimal strategy should be reconsidered only at mortality values of less than 8% for patients without comorbidity and less than 12% for patients with comorbidity. In order to fully appreciate the CEA, it is necessary to understand the inherent limitations of the simplification of a decision model. By necessity, conditional independence of the diagnostic tests was assumed (Appendix). However, the sensitivity and specificity of a test may not be constant but rather depend on the results of a preceding test. Data on the accuracy of the various diagnostic tests are generally insufficient to control for this effect. Although life expectancy, especially if corrected for the quality of life, is the generally preferred outcome measure for cost-effectiveness analyses, patients with PE have a wide variety of severe comorbid conditions. Literature data are insufficient to make valid assumptions concerning the quality-adjusted life expectancy of these patients. In addition, costs and seriousness of complications, costs of dying, patient and physician satisfaction, availability and feasibility of diagnostic modalities, impact of a diagnostic modality on costs and duration of hospital stay, and implications of alternative diagnoses are all factors that may influence decisions in clinical practice.
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Using incremental marginal cost-effectiveness to determine the optimally cost-effective diagnostic strategy also has several limitations. Society's willingness to pay for an additional life saved is arbitrarily set and best used to compare different health-care programs. Using this parameter as a limit for the incremental cost-effectiveness of diagnostic strategies for an isolated clinical problem is in conflict with a health-care system with limited financial resources (23,24).
The results of the updated CEA reiterate a prominent role for helical CT in the diagnosis of PE. The D-dimer assay reduces the cost-effectiveness of diagnostic strategies for PE, especially in patients with comorbidity. Helical CT preceded by ultrasound (US/CT) appears to be the most cost-effective diagnostic strategy for PE. This is true both for patients with and without comorbidity and holds for a wide range of mortality values of untreated PE. The optimal strategy changes only at a low mortality value of untreated PE, which is, unfortunately, an unknown factor. Theoretic recommendations for an optimally cost-effective algorithm can therefore serve as best approximations only.
Assumptions on Diagnostic Strategies For all diagnostic strategies, the following basic principles were assumed: 1. Helical CT or pulmonary angiography serve as final tests to detect or exclude PE. 2. If DVT is detected by ultrasound, no further testing is considered necessary and anticoagulant therapy is initiated. Otherwise, the next diagnostic procedure in the algorithm will be performed. 3. The D-dimer test is used to exclude thromboembolic disease. If it is negative, no further diagnostic action is taken and no anticoagulant treatment is given. A positive D-dimer result prompts the next test in the algorithm. 4. Normal perfusion scintigraphy (P-scan) virtually excludes PE, and no additional testing is performed. The presence of perfusion defects prompts the next diagnostic procedure. 5. Ventilation scintigraphy (V-scan) is performed only after an abnormal P-scan. A high probability V/P-scan is taken as evidence of PE. All other V/P results are nondiagnostic and prompt the next test.
DIAGNOSTIC ALGORITHMS IN PULMONARY EMBOLISIV
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