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Evaluation of diagnostic tests: from accuracy to outcome
Lijmer, J.G.
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Citation for published version (APA):Lijmer, J. G. (2001). Evaluation of diagnostic tests: from accuracy to outcome.
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Download date: 03 Jun 2020
Cost-effectivenes ss of noninvasiv e diagnosti c
strategie ss in pulmonar y embolism .
Jeroenn G. Lijmer, Wilbert B. van den Hout, Wouter de Monye,
Bernd-Jann Sanson, Paul Verboom, Martin H. Prins, Men no V. Huisman,
Peterr M.T. Pattynama and Harry R. Biiller
onn behalf of the ANTELOPE study group
Submitted Submitted
ChapterChapter 6
Backgroun dd New non-invasive tests, such as d-dimer measurement, clinical
probabilityy estimates, (serial) compression ultrasonography and spiral CT, are
advocatedd to reduce the number of pulmonary angiograms in patients with
suspectedd pulmonary embolism. We wanted to compare the effectiveness and costs
off various non-invasive diagnostic strategies with the standard strategy using
pulmonaryy angiography.
Method ss and Result s A decision model was developed representing 12 diagnostic
strategies:: 2 strategies with pulmonary angiography, 8 non-invasive strategies and 2
referencee strategies. Data on the sensitivity, specificity and costs of spiral CT,
compressionn ultrasonography, ventilation-perfusion lungscanning and triage tests
weree extracted from a large prospective study. These were supplemented with data
fromm the literature on the sensitivity and specificity of serial ultrasonography and
clinicall outcomes. For each strategy 3-month mortality, costs per patient, test
characteristics,, percentage of performed angiograms, and total proportion of treated
patientss (treatment rate).
Cost-effectivee non-invasive diagnostic strategies were: 1) triage test, perfusion
scan,, spiral CT, and serial compression ultrasonography, 2) triage test, ventilation-
perfusionn scan and serial compression ultrasonography and 3) triage test, spiral CT,
andd serial compression ultrasonography. The standard strategy perfusion-ventilation
lungg scanning, ultrasonography and angiography combined with a triage test had a
0.02%% lower mortality but at higher costs.
Thee differences in mortality between strategies with serial ultrasonography and
strategiess with angiography depended on the clinical course of subsegmental
emboli,, the sensitivity of the serial compression ultrasonography and the procedure
relatedd mortality of the angiography.
Conclusion ss The expected mortality of the evaluated strategies with serial
ultrasonographyy is in the same range as that for the standard strategy with
pulmonaryy angiography as the final test. Especially, the combination of serial
ultrasonographyy following either a spiral CT or a non-diagnostic lung scan seems
promising. .
74 4
Cost-effectivenessCost-effectiveness of noninvasive diagnostic strategies in pulmonary embolism
Introductio n n Suspectedd pulmonary embolism, with an estimated incidence of 2 to 3 per 1000
inhabitantss annually, is a common diagnostic problem in the western world.1 The
valuee of the ventilation-perfusion lungscanning for the diagnostic work-up has been
establishedd in several large studies.2,3 Nevertheless in approximately 50% of patients
thee results of ventilation-perfusion lungscanning are inconclusive and considered as
non-diagnostic.. In these patients further objective tests are needed to confirm or
refutee the diagnosis. The recommended strategy is to perform a single compression
ultrasonographyy in search of deep leg vein thrombosis, followed by a pulmonary
angiographyy in case of a normal result. Since ultrasonography is not a very sensitive
testt in this clinical setting, angiography is indicated in most patients with a non-
diagnosticc ventilation-perfusion lungscan.4 Contrary to these recommendations,
surveyss of clinical practice have shown that pulmonary angiography is frequently not
performed,, due to its invasive character and lack of direct availability in many
hospitals.55 7 Several new non-invasive tests, such as d-dimer measurement, clinical
probabilityy estimates and spiral CT, are advocated to reduce the number of
pulmonaryy angiograms in patients with suspected pulmonary embolism.3 Moreover,
recentt reports have indicated that replacing angiography by serial testing for deep
venouss thrombosis could be a safe alternative strategy in patients with a non-
diagnosticc ventilation-perfusion lungscan.9,10
Wee combined the clinical results of these studies with the diagnostic
performancee of several tests as evaluated in a large prospective patient-based study
too compare the 3-month mortality and the cost-effectiveness of several non-invasive
diagnosticc strategies with the standard strategy using pulmonary angiography.
Method s s
DecisionDecision Model
AA decision model was developed representing 12 strategies for the diagnostic work-
upp of patients suspected of pulmonary embolism. The model contained the
standardd strategy (ventilation-perfusion lungscanning, ultrasonography and
pulmonaryy angiography), the standard strategy without pulmonary angiography, the
standardd strategy with spiral CT angiography instead of pulmonary angiography, 3
diagnosticc strategies with serial compression ultrasonography, and 2 reference
strategiess (no treatment and treating all patients without diagnostic testing ). In an
additionall 4 strategies, the effect of a 'triage test', to rule out pulmonary embolism
inn an easy manner at the beginning of the diagnostic work-up was evaluated.
75 5
ChapterChapter 6
Commonn rules applicable to each strategy were: The diagnosis of pulmonary
embolismm was ruled out by a normal pulmonary angiogram, a normal perfusion
scan,, or a normal triage test. The diagnosis of pulmonary embolism was established
byy an abnormal angiogram, a high probability ventilation-perfusion scan, an
abnormall spiral CT, or an abnormal ultrasonography of the deep leg veins. All other
testt results led to the next test in the strategy. The final test of a strategy was used to
rulee out as well as to establish the diagnosis pulmonary embolism.
Wee calculated 3-month mortality, costs per patient, test characteristics,
percentagee of performed angiograms, and total proportion of treated patients
(treatmentt rate) of each strategy. Subsequently incremental cost-effectiveness ratios
forr the diagnostic strategies were calculated as the incremental cost per patient
dividedd by the reduction of 3-month mortality for one strategy relative to the next
leastt expensive strategy. Strategies with higher costs and a higher mortality were
ruledd out by simple dominance. If a strategy was less effective and had a higher
incrementall cost-effectiveness ratio than a more expensive strategy, it was ruled out
byy extended dominance.11
Thee results of a large prospective study, the ANTELOPE study, on the sensitivity,
specificity,, costs of various diagnostic tests for pulmonary embolism formed the basis
forr this analysis. These were supplemented with data from the literature on the
sensitivityy and specificity of serial ultrasonography and clinical outcomes.
JestJest characteristics
Dataa on the diagnostic accuracy of clinical probability assessment, a D-dimer test,
compressionn ultrasonography, ventilation-perfusion lungscanning and Spiral CT
weree obtained from the ANTELOPE study. Details of this large prospective study are
describedd elsewhere.12"14 Briefly, both in- and outpatients with a clinical suspicion of
pulmonaryy embolism were eligible for the study. A detailed clinical history, physical
examination,, assessment of clinical probability for pulmonary embolism, a D-dimer
test,, a compression ultrasonography and a ventilation-perfusion lungscan were
performedd in all patients. Spiral CT angiography was only performed in patients with
ann abnormal perfusion scan. Pulmonary embolism was excluded by a normal
perfusionn lungscan or a normal pulmonary angiography. The diagnosis was
establishedd in case of an abnormal angiography or a high-probability VQ scan. All
casess of pulmonary embolism (PE) were reviewed to determine the level of the
largestt obstruction with pulmonary angiography or spiral CT into either
subsegmentalsubsegmental pulmonary embolism, i.e. largest embolus found in a subsegmental
pulmonaryy artery, or segmental pulmonary embolism, i.e. largest embolus found in
segmentall or larger pulmonary artery.
76 6
Cost-effectivenessCost-effectiveness of noninvasive diagnostic strategies in pulmonary embolism
Thee sensitivity for segmental pulmonary embolism, the sensitivity for subsegmental
pulmonaryy embolism and the specificity for pulmonary embolism were calculated
forr each test. For the calculation of the sensitivity of the perfusion scan both a
segmentall and subsegmental defects were regarded as abnormal. The sensitivity and
specificityy of the ventilation scan were calculated for the subgroup of patients with
ann abnormal perfusion lungscan. To obtain an estimation of the specificity of the
spirall CT for the entire group {since a spiral CT was not performed in case of a
normall perfusion scan) we assumed that in these patients the spiral CT would also
havee been normal. In addition, sensitivities and specificities of the spiral CT and
ultrasonographyy conditional on previous test results were calculated. The sensitivity
andd specificity of the 'triage test' were based on the combination of a clinical
probabilityy and a d-dimer test (Tinaquant®) requiring both a normal D-dimer assay
Tabl ee 1 Results from the prospective study
Valuess of base case analysi s (%)
PrevalencePrevalence pulmonary embolism
Subsegmental l
Segmental l
TriageTriage test* Sensitivityy segmental
Sensitivityy subsegmental
Specificity y
PerfusionPerfusion scan
Sensitivityy segmental
Sensitivityy subsegmental
Specificity y
VentilationVentilation scan
Sensitivityy segmental
Sensitivityy subsegmental
Specificity y
Ultrasonography Ultrasonography
Sensitivityy segmental
Sensitivityy subsegmental
Specificity y
SpiralSpiral CT
Sensitivityy segmental
Sensitivityy subsegmental
Specificity y
Independen t t
29.6 6
6.8 8 22.8 8
100 0 100 0 12 2
98 8 97 7 65 5
NA A NA A NA A
26 6 7 7 97 7
86 6 21 1 95 5
1 1
abnormalabnormal perfusion scan scan 87 7 83 3 84 4
non-diagnostic non-diagnostic VQVQ lungscan
0 0
20 0 97 7
abnormalabnormal perfusion scan scan 86 6
21 1 85 5
Dependen tt *
l l
abnormalabnormal perfusion scan + normalnormal SCT
8 8
10 0 99 9
non-diagnostic non-diagnostic VQVQ lungscan + normal US
58 8
25 5 86 6
NAA is not applicable,' normal if Clinical Assessment < 20% and D-dimer < 500 ng/ml, t sensitivities and specificitiess were recalculated in the subgroups of patients with the test results mentioned in the heading.
77 77
ChapterChapter 6
(<< 500 ng/ml) and a low clinical probability estimate (<20%) to rule out pulmonary
embolismm at initial evaluation. The tests characteristics calculated from the results of
thee Antelope study are listed in Table 1.
Forr the sensitivity of serial ultrasonography in our analysis, we used the results
fromm the prospective study on the sensitivity of the first compression
ultrasonographyy and the results of Well and colleagues on the combined sensitivity
off subsequent ultrasonographies.10 They reported a sensitivity of subsequent
ultrasonographiess of 82%. The specificity of subsequent ultrasonographies was
estimatedd to be 98% on the basis of reports on the specificity of a single
compressionn ultrasonography.15
Ass pulmonary angiography is widely accepted as the reference standard for
diagnosingg pulmonary embolism, we assumed a sensitivity and specificity of 100%.
ClinicalClinical Course
Onee early randomized controlled trial showed a relative risk of 0.14 for
anticoagulantt treatment compared to no treatment with a baseline mortality of
26%.166 In a recent review the 3-month mortality rate in patients diagnosed with
pulmonaryy embolism and treated with anticoagulants was 2.3%, which would
translatee to a mortality of untreated pulmonary embolism of 16%.17 Moreover, the
mortalityy of subsegmental pulmonary embolism could be lower.18 We assumed a
mortalityy for untreated segmental pulmonary embolism of 18% and for untreated
subsegmentall pulmonary embolism 9%. The 3-month risk of a fatal bleeding during
anticoagulantt treatment is, based on a weighted average of four large trials, 0.5%.19" 222 The mortality of treated segmental pulmonary embolism and subsegmental
pulmonaryy embolism were estimated 2.3 and 1.4%, both percentages including a
0.5%% risk of fatal bleeding. The procedure related mortality of angiography was
estimatedd to be 0.2%.23'2A On basis of the Antelope data the prevalence of PE in
patientss suspected of this disease was estimated 30% of which 77% segemental or
largerr and 23% sybsegmental disease. All base case values are listed in table 2.
Costs Costs
Costss were calculated from the perspective of the healthcare system. In four centers
participatingg in the study the use of resources was prospectively measured. Integral
costss were calculated for the relevant medical services, taking into account the costs
directlyy related to the performance of the service (personnel, medical materials and
equipment)) as well as costs of the institutional infrastructure (laboratories and
overhead). .
78 8
Cost-effectivenessCost-effectiveness of noninvasive diagnostic strategies in pulmonary embolism
Dataa on the hourly rate of staff was obtained by calculating average wages for the
stafff involved based on the salary rates of 1998 of the hospitals involved. The
averagee costs of material and equipment were calculated from info of the Financial
Administrationss (1998) and Hospital Information Systems. The costs of personnel,
materialss and equipment were combined with the resource utilization data to
calculatee the median costs of each diagnostic test. The costs of treatment include
thee costs of 7-day hospital stay for heparin treatment, costs of 3 months
anticoagulantt treatment, and costs for hospital admission in case of non-fatal
bleeding.. The costs of hospital stay for diagnosis, on average 2,5 days, were not
takenn into account, as they would have no influence on the difference in total costs.
Thee relevant costs are summarized in Euro's in table 3. (1 € ~ 0.88US$).
Tablee 2. Data from literature
Variablee Base case value (%) Sensitivity analysis SerialSerial Ultrasonography
Sensitivityy 82 57-96 Specificityy 98
Angiography Angiography Sensitivityy 100 Specificityy 100 Mortalityy angiography 0.2 0-0.5
NaturalNatural course (mortality)
Segmentall PE untreated 18 26 Segmentall PE treated 1.8*
Sub-segmentall PE untreated 9 5-18 Sub-segmentall PE treated 0.9* 0.5 -1.8 NoPEE 0
Riskk of fatal bleeding during treatment 0.5
PEE indicates Pulmonary Embolism. * The risk of fatal bleeding during treatment excluded.
T a b l ee 3 . Costs
Categoryy Costs per unit in EUR0(€) Triagee test — ~~ 6~ Perfusionn scan 120 Ventilationn scan 254 Ultrasonographyy 47 Seriall ultrasonography 142
Spirall CT 216 Angiographyy 598
Costss of treatment 1628
79 9
ChapterChapter 6
SensitivitySensitivity analysis
Thee robustness of the model's results was tested by varying the value of one variable
att a time and recalculating the expected outcome. Table 2 shows the range for
whichh the values derived from the literature were varied. The mortality of treated
andd untreated subsegmental pulmonary embolism were varied in conjunction, so
thatt the relative risk of anticoagulant treatment remained constant.
Byy varying the mortality of subsegmental pulmonary embolism the ratio of
subsegmentall and segmental pulmonary embolism was also indirectly varied. As by
assumingg a mortality of 18% for subsegmental pulmonary embolism all grades of
pulmonaryy embolism are considered prognostically equal.
Thee sensitivity of the serial compression ultrasonography was varied over the
rangee of the 95% confidence interval. The effect of the assumption of a normal
spirall CT in case of a normal perfusion scan was examined by recalculating the
resultss with a specificity of 85% for the spiral CT, the specificity in the subgroup of
patientss in which the test was actually performed.
Result s s
Basee case analysis
Thee percentages of patients with segmental and subsegmental pulmonary embolism
whichh are correctly identified and subsequently treated with anticoagulants by each
strategyy are listed in Table 4. The standard strategy with pulmonary angiography and
triagee test had the highest sensitivity for the detection of pulmonary embolism.
However,, this strategy has as disadvantage the high rate of angiographies necessary
(Tablee 2). The non-invasive strategy, spiral CT with serial ultrasonography, also had a
highh sensitivity, yet limited to the detection of segmental or larger pulmonary
emboli.. Combinations of ventilation-perfusion scan and serial compression
ultrasonographyy are non-invasive strategies with a high sensitivity for subsegmental
orr smaller emboli.
Thee expected outcomes of the diagnostic strategies evaluated are presented in
Tablee 5. All strategies show a substantial reduction of the 4.7% mortality associated
withh no diagnostic intervention and no treatment to 1.3% or lower (relative risk
reductionn > 70%). The non-invasive diagnostic strategy with the lowest costs
consistss of a ventilation-perfusion lungscan combined with a single compression
ultrasonographyy in case of a non-diagnostic result. This strategy has a mortality of
1.28%.. A reduction of this mortality can be obtained by using a perfusion scan
followedd by spiral CT and serial compression ultrasonography to 0.87%. A slightly
largerr reduction is obtained by the combination of a ventilation-perfusion lungscan
80 0
Cost-effectivenessCost-effectiveness of noninvasive diagnostic strategies in pulmonary embolism
andd serial compression ultrasonography (0.83%). The costs of both strategies are
reducedd in case a triage test to rule out pulmonary embolism at an early stage is
usedd without changing the mortality. With a triage test the incremental cost-
effectivenesss ratios of these two strategies are € 11 900 and € 27 500 per life saved
respectively.. The non-invasive strategy with the lowest mortality (0.79%) is spiral CT
followedd by serial compression ultrasonography, in case of a negative result,
combinedd with a 'triage' test resulting in a incremental cost-effectiveness ratio of
€€ 194 200. The non-invasive strategy with spiral CT as final test has a high mortality
off 1.0% compared to the other strategies. The standard invasive strategy of VQ scan,
ultrasonographyy and pulmonary angiography is more cost-effective if it is preceded
byy a 'triage' test resulting in a mortality of 0.77% and a cost-effectiveness ratio of
€2199 700.
Tablee 4. Diagnostic characteristics of strategies to detect pulmonary embolism
Strateg y y
standardstandard strategy
VQQ scan+ CUS+ Angio
standardstandard strategy with a triage test
Triagee test+VQ scan+ CUS+ Angio
StrategiesStrategies with serial ultrasonography
Spirall CT+serial CUS
VQQ scan+ serial CUS
QQ scan+ Spiral CT+ serial CUS
Triagee +Spiral CT+ serial CUS
Triagee +VQ scan+ serial CUS
Triagee +Q scan+ Spiral CT+ serial CUS
otherother non-invasive strategies
VQQ scan+ CUS+ Spiral CT
VQQ scan+ CUS
Sensitivit y y
PE E
98 8
98 8
98 8 96 6 96 6 98 8 96 6 96 6
93 3 85 5
Sensitivit y y
segm . . PE E
96 6
97 7
87 7 94 4 85 5 87 7 94 4 85 5
87 7 83 3
Specificit y y
PE E
94 4
94 4
91 1 93 3 94 4 92 2 94 4 95 5
90 0 94 4
Treatmen tt Anglo' s
rate e performe d d
33.55 24
32.99 21
34.5 5
33.2 2
31.8 8
33.8 8
32.6 6
31.3 3
34.4 4
29.6 6
pulmonaryy angiography (Angio), perfusion lung scan (Q scan)
81 1
ChapterChapter 6
Tabl ee 5. Base Case Analysis of diagnostic strategies for patients suspected of
pulmonaryy embol ism
Strategyy Costs (€) Mortality Change in Change in Incremental Cost-
(%)) marginal marginal Effectiveness Ratio
Costs{€)) Mortality(%)
VQQ scan+ CUS
Triagee +Q scan+ Spiral CT+ serial CUS
Triagee +VQ scan+ serial CUS
QQ scan+ Spiral CT+ serial CUS
VQQ scan+ serial CUS
Triagee +Spiral CT+ serial CUS
VQQ scan+ CUS+ Spiral CT
Spirall CT+ serial CUS
Triagee test+VQ scan+ CUS+ Angio
VQQ scan+ CUS+ Angio
724 4
772 2
785 5
793 3
806 6
849 9
857 7
883 3
898 8
930 0
1.28 8
0.87 7
0.83 3
0.87 7
0.83 3
0.79 9
1.00 0
0.80 0
0.77 7
0.78 8
48 8
13 3
8 8
21 1
64 4
8 8
34 4
49 9
32 2
-0.41 1
-0.04 4
0.05 5
0.00 0
-0.04 4
0.21 1
0.01 1
2 2
0.01 1
11900 0
27500 0
dominated d
dominated d
194200 0
dominated d
dominated d
219700 0
dominated d
ReferenceReference strategies
Treatt All 1628 0.97
Treatt None 4.72
Tabl ee 6 . Sensitivity analyses of diagnostic strategies to detect pulmonary embol ism
Strategyy Specificity Spiral CT= Sensitivity serial US Mortality subsegmental 85%% =57% PE=5%
VQQ scan+ CUS
Triagee +Q scan+ Spiral CT+ serial CUS
Triagee +VQ scan+ serial CUS
QQ scan+ Spiral CT+ serial CUS
VQQ scan+ serial CUS
Triagee +Spiral CT+ serial CUS
VQQ scan+ CUS+ Spiral CT
Spirall CT+ serial CUS
Triagee test+VQ scan+ CUS+ Angio
VQQ scan+ CUS+ Angio
** Costs increased to 936
Mortality y
(%) ) 1.28 8
0.87 7
0.83 3
0.87 7
0.83 3
0.82 2
1.00 0
0.83 3
0.77 7
0.78 8
Marg. . C/EE Ratio
11900 0
27500 0
dom. .
dom. .
dom.* *
dom. .
dom. .
204500 0
dom. .
Mortality y
(%) ) 1.28 8
1.08 8
0.97 7
1.08 8
0.97 7
1.0 0
1.0 0
1.0 0
0.77 7
0.78 8
Marg. . C/EE Ratio
--8500 0
24000 0
dom. .
dom. .
dom. .
dom. .
dom. .
66400 0
dom. .
Mortality y
(%) ) 1.21 1
0.81 1
0.79 9
0.81 1
0.79 9
0.74 4
0.94 4
0.74 4
0.74 4
0.75 5
Marg. . C/EE Ratio
12000 0
57900 0
dom. .
dom. .
dom. .
dom. .
127800 0
dom. .
dom. .
82 2
Cost-effectivenessCost-effectiveness of noninvasive diagnostic strategies in pulmonary embolism
SensitivitySensitivity analysis
Increasingg the mortality for untreated subsegmental and segmental pulmonary
embolismm from the base case values (9 and 18%) to 13 and 26% has no influence
onn the relative order of the strategies. Decreasing the specificity of spiral CT to 85%
resultss in a marginal increase in mortality and an increase in costs of three strategies
usingg a spiral CT without a previous perfusion lungscan. The only cost-effective
strategyy with a spiral CT in this case is a combination of a triage test, perfusion scan,
spirall CT and serial compression ultrasonography.
Inn case the combined sensitivity of subsequent ultrasonographies is decreased to
57%% (base case value 82%) the expected mortalities of all strategies with serial
compressionn ultrasonography increase. The incremental difference in mortality
betweenn cost-effective non-invasive and invasive strategies increases from 0.02% to
0.22 %. The most cost-effective non-invasive strategy is in this case a combination of
aa triage test, perfusion-ventilation lungscan and serial ultrasonography (Table 6).
Thee difference between non-invasive and invasive strategies also increases in
favorr of the latter when zero mortality for angiography is assumed (base case value
0.2%).. The most cost-effective non-invasive strategy is a combination of a triage test,
perfusion-ventilationn lungscan and serial ultrasonography. The incremental cost-
effectivenesss ratio between the standard strategy with angiography combined with a
triagee test and the best non-invasive strategy reduces to €115 600. Changing the
mortalityy of untreated subsegmental pulmonary embolism from 9 to 18%, resulting
inn equal mortality rates for subsegmental and segmental pulmonary embolism,
increasess the mortality rate of all strategies. The incremental mortality between the
bestt non-invasive and invasive strategies increases to 0.07 %, resulting in a
incrementall cost-effectiveness ratio of € 165 700.
Whenn the mortality of untreated subsegmental pulmonary embolism is changed
too 5% (base case value=9%), the differences between noninvasive and invasive
strategiess decreases, resulting in dominance of non-invasive strategies. The strategy
withh the lowest mortality at the lowest cost is than spiral CT combined with serial
ultrasonographyy (0.74%) (Table 6).
Thee same non-invasive strategies are also dominant in case the mortality of the
angiographyy is increased to 0.5% and when the combined sensitivity of subsequent
ultrasonographiess is increased to 96%. In the first case the mortality of all strategies
withh pulmonary angiography increases at least to 0.84%, in the latter the mortality of
strategiess with serial ultrasonography decreases to at least 0.76%.
83 3
ChapterChapter 6
Discussio n n Ourr analysis shows that the expected mortality of strategies with serial
ultrasonographyy of the deep leg veins is slightly larger as the mortality of
conventionall strategies with pulmonary angiography as the final test in patients with
suspectedd pulmonary embolism. The latter approaches have the disadvantages of
higherr costs, limited feasibility and additional morbidity associated with the
angiography,, resulting in a high incremental cost-effectiveness ratio. The sensitivity
analysess suggest that these results depend on the clinical course of subsegmental
emboli,, the sensitivity of the serial compression ultrasonography and the procedure
relatedd mortality of the angiography.
AA lower sensitivity for the subsequent ultrasonographies, zero mortality for
pulmonaryy angiography and a higher mortality for subsegmental emboli increased
thee differences in mortality between non-invasive and invasive strategies in favor of
thee latter. However, the differences remained small (<0.2%). The largest difference
off 0.2% was observed in case the combined sensitivity of serial ultrasonography,
whichh was based on the results of a single study10, was reduced to 57%. This shows
thatt even if in future studies this sensitivity of serial ultrasonography would proof to
bee considerably lower, our conclusions remain valid. Non-invasive strategies were
dominantt (lower mortality and lower costs) over invasive strategies in case the
mortalityy of angiography was increased to 0.5%, the mortality of subsegmental
embolii was decreased to 5% or the sensitivity of serial ultrasonography would be
higherr than reported.
Inn the four strategies in which we examined the cost-effectiveness of a triage-test,
thee addition of a triage test lead to a reduction of the cost without compromising the
effectivenesss of the strategy. This a result of the high sensitivity of the triage test, a
combinationn of clinical assessment and a d-dimer assay, we used. In a separate
sensitivityy analysis we examined the minimal test characteristics of a triage test to be
dominantt over a strategy without such a test (data not shown). This analysis
suggestedd that small differences in sensitivity cause differences in mortality, whereas
thee specificity can be varied over a large range of values without changing the
mortalityy of the strategy with a triage test significantly. The sensitivity had to be at
leastt 99% (for a non-invasive strategy) to be dominant. In case the sensitivity was as
loww as 95% the differences in mortality remained small (< 0.2%). All combinations
leadd to a cost reduction as expensive tests are only performed in a subset of
patients. .
Threee recent cost-effectiveness analyses have also compared several non-invasive
diagnosticc strategies with the standard strategy using angiography.8' 25' 26 None of
84 4
Cost-effectivenessCost-effectiveness of noninvasive diagnostic strategies in pulmonary embolism
thesee studies examined a combination of spiral CT with serial ultrasonography, or
madee a distinction between the clinical course of segmental and subsegmental
pulmonaryy embolism. The latter is important as the analysis of our prospective data
showedd that the diagnostic characteristics of the different tests vary largely for
segmentall or subsegmental emboli. In one analysis a strategy of a single
ultrasonographyy followed by a spiral CT had the lowest mortality.8 However, they
assumedd a higher sensitivity of ultrasonography, and also a higher sensitivity and
specificityy for Spiral CT than we observed in the prospective.
Hulll and colleagues evaluated strategies with serial ultrasonography and serial
impedancee plethysmography using data derived from a study of patients who
participatedd in the collaborative Prospective Investigation of Pulmonary Embolism
Diagnosiss (PIOPED).25 In their strategies, serial non-invasive leg testing was only
performedd in patients with an adequate cardiorespiratory reserve. Patients with an
inadequatee reserve underwent a pulmonary angiography after a single normal non-
invasivee leg test. They concluded that strategies with serial non-invasive leg testing
costt less per correctly identified patient than conventional strategies with
angiography,, which is similar to our findings.
Perrierr and colleagues examined the value of ultrasonography and d-dimer in
thee diagnostic workup of pulmonary embolism and concluded that this combination
couldd be used before as well as after lung scanning to reduce the number of
requiredd angiograms.26 However, angiograms were still required in 26% of the
patients.. In case non-diagnostic ventilation-perfusion lungscans were subdivided
intoo intermediate and low categories this percentage could be reduced to 4%. They
evaluatedd only one non-invasive strategy, in which intermediate ventilation-
perfusionn lungscans were treated, resulting in a very high false positive rate (24.7%).
Sincee a tendency exists to treat patients with pulmonary embolism longer than 3
monthss with vitamin K antagonists, thereby increasing the burden and costs of
treatment,, such a high false positive rate is likely to be clinically unacceptable.
Onee of the limitations of our analysis is that we did not calculate the morbidity
associatedd with each strategy. In these strategies the three main sources of morbidity
are,, non-fatal bleedings during anticoagulant treatment, recurrent pulmonary
embolismm and severe complications of angiography. The degree of morbidity of
eachh strategy is therefore directly related to the number of treated patients, false
negativee patients and angiograms performed. As we do report the treatment rate,
thee sensitivity and the number of angiograms required for each strategy it is possible
too assess which strategies have a potential for a high morbidity rate.
Wee also did not take into account waiting costs, which occur due to the delay of
thee diagnosis in patients submitted for serial ultrasonography. From a societal
perspective,, these are associated with lost or impaired ability to work. The costs of
85 5
ChapterChapter 6
alll strategies with serial testing would then be higher. However, this would also
applyy to all strategies with angiography as the latter have more morbidity due to the
proceduree itself.
Theree are no empirical data on the use of serial ultrasonography in patients with
inadequatee cardiorespiratory reserve. As the cardiorespiratory state was not
recordedd in the prospective study it was not possible to examine the effect of a
differentt diagnostic modality for this subgroup of patients.
However,, the amount of patients excluded from serial ultrasonography in the
studyy of Wells et al10 was small (34/736). In clinical practice there will always be a
smalll number of patients in which the physician will consider it unsafe to delay
diagnosiss by more than 24 hours. In that case an angiography is preferred over serial
ultrasonography,, raising the costs of such strategies with minimal changes in
mortality. .
Inn general, the advantage of strategies with serial ultrasonography is that a large
amountt of pulmonary angiographies can be avoided. However this is associated
withh a delay of the diagnosis in some patients and a considerable number of normal
ultrasonographies.. A further search for new tools is necessary for an easy exclusion
off the diagnosis of pulmonary embolism in 1-day in all patients. Non-invasive
diagnosticc strategies with serial leg testing are feasible, safe and effective in
comparisonn with conventional strategies. Especially, the combination of serial
ultrasonographyy following either a spiral CT or a non-diagnostic lung scan seems
promising.. However, more large prospective management studies with clinical
follow-upp are needed before these strategies are disseminated in clinical practice.
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