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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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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


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


Specificity y

VentilationVentilation scan



Specificity y

Ultrasonography Ultrasonography



Specificity y

SpiralSpiral CT



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


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


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







Spirall CT+ serial CUS



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







Spirall CT+ serial CUS



** 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


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


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.

Reference s s 1.. Anderson FA, Jr., Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et

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5.. Egermayer P, Town CI. Compliance with guidelines for the investigation and management off patients with suspected pulmonary embolism at Christchurch Hospital. N Z Med J 1998;111:70-3. .

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11 .. Gold MR, SiegelJE, Russell LB, Weinstein MC. Cost-effectiveness in Health and Medicine. Neww York: Oxford University press, 1996.

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ChapterChapter 6

2 1 .. Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, et al. A comparison off low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism.. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations danss I'Embolie Pulmonaire. N Engl J Med 1997;337:663-9.

22.. Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, et al. Treatmentt of venous thrombosis with intravenous unfractionated heparin administered inn the hospital as compared with subcutaneous low- molecular-weight heparin administeredd at home. The Tasman Study Group. N Engl J Med 1996;334:682-7.

23.. van Beek EJ, ReekersJA, Batchelor DA, Brandjes DP, Buller HR. Feasibility, safety and clinicall utility of angiography in patients with suspected pulmonary embolism. Eur Radioll 1996;6:415-9.

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