Different Imaging Strategies in Patients With Possible
Basilar Artery Occlusion
Cost-Effectiveness Analysis
Sebastian E. Beyer; Myriam G. Hunink, MD, PhD; Florian Schöberl, MD;
Louisa von Baumgarten, MD; Steffen E. Petersen, MD, DPhil; Martin Dichgans, MD;
Hendrik Janssen, MD; Birgit Ertl-Wagner, MD; Maximilian F. Reiser, MD;
Wieland H. Sommer, MD, MPH
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Background and Purpose—This study evaluated the cost-effectiveness of different noninvasive imaging strategies in
patients with possible basilar artery occlusion.
Methods—A Markov decision analytic model was used to evaluate long-term outcomes resulting from strategies using
computed tomographic angiography (CTA), magnetic resonance imaging, nonenhanced CT, or duplex ultrasound with
intravenous (IV) thrombolysis being administered after positive findings. The analysis was performed from the societal
perspective based on US recommendations. Input parameters were derived from the literature. Costs were obtained
from United States costing sources and published literature. Outcomes were lifetime costs, quality-adjusted life-years
(QALYs), incremental cost-effectiveness ratios, and net monetary benefits, with a willingness-to-pay threshold of
$80 000 per QALY. The strategy with the highest net monetary benefit was considered the most cost-effective. Extensive
deterministic and probabilistic sensitivity analyses were performed to explore the effect of varying parameter values.
Results—In the reference case analysis, CTA dominated all other imaging strategies. CTA yielded 0.02 QALYs more than
magnetic resonance imaging and 0.04 QALYs more than duplex ultrasound followed by CTA. At a willingness-to-pay
threshold of $80 000 per QALY, CTA yielded the highest net monetary benefits. The probability that CTA is cost-effective
was 96% at a willingness-to-pay threshold of $80 000/QALY. Sensitivity analyses showed that duplex ultrasound was costeffective only for a prior probability of ≤0.02 and that these results were only minimally influenced by duplex ultrasound
sensitivity and specificity. Nonenhanced CT and magnetic resonance imaging never became the most cost-effective strategy.
Conclusions—Our results suggest that CTA in patients with possible basilar artery occlusion is cost-effective. (Stroke. 2015;46:1840-1849. DOI: 10.1161/STROKEAHA.115.008841.)
Key Words: cost-effectiveness analysis ◼ economics ◼ stroke
B
asilar artery occlusion (BAO) is a life-threatening condition. Without treatment, a fatal outcome must be expected
in >90% of patients.1,2 Even if treated, mortality rates of 30%
to 40% have been reported.3,4 In view of these poor outcomes,
treatment, if attempted, must not be delayed.5 Notably, ≈75%
of the survivors have a favorable functional long-term outcome with an acceptable quality of life.1
Symptoms of BAO include almost the entire spectrum of
neurological deficits, such as altered consciousness, dysarthria, diplopia, dysphagia, ataxia, visual (field) disturbances,
sensory deficits, and paresis.3 However, the main presenting
and sometimes even only symptoms, especially in the early
stage, can be vertigo or unspecific dizziness and unsteadiness of stance and gait. The often subacute symptom onset,
the varying time course, as well as the subtle, unspecific, and
partly fluctuating symptoms in up to >90% of the patients can
be challenging for the clinician and delay correct diagnosis.6
Depending on the clinical setting, nonenhanced computed tomography (NECT) or transcranial Doppler and colorcoded duplex ultrasound (DUS) are used in the acute setting,7
Received January 21, 2015; final revision received April 1, 2015; accepted April 2, 2015.
From the Institute of Clinical Radiology (S.E.B., B.E.-W., M.F.R., W.H.S.), Department of Neurology (F.S., L.B.), Institute for Stroke and Dementia
Research (M.D.), and Department of Neuroradiology (H.J.), Ludwig-Maximilian University of Munich Hospitals, Munich, Germany; Advanced
Cardiovascular Imaging, William Harvey Research Institute, National Institute for Health Research, Cardiovascular Biomedical Research Unit at Barts,
The London Chest Hospital, London, United Kingdom (S.E.P.); Department of Radiology (M.G.H.) and Department of Epidemiology (M.G.H.), Erasmus
University Medical Center, Rotterdam, The Netherlands; and Department of Health Policy and Management, Harvard School of Public Health, Harvard
University, Boston, MA (M.G.H.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
115.008841/-/DC1.
Correspondence to Wieland H. Sommer, MD, MPH, Institute of Clinical Radiology, Ludwig-Maximilian University of Munich Hospitals, Marchioninistr.
15, 81377 Munich, Germany. E-mail [email protected]
© 2015 The Authors. Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium,
provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.008841
1840
Beyer et al Basilar Artery Occlusion Cost-Effect Analysis 1841
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especially if the pretest probability of BAO is relatively low.
However, DUS of the basilar artery is uninterpretable in ≤50%
of patients if standard noncontrast enhanced techniques are
applied.8 In NECT, the hyperdense basilar artery sign alone
has a low sensitivity ranging from 61% to 71%.9,10 Direct
assessment using the more expensive computed tomographic
angiography (CTA) or magnetic resonance (MR) angiography
may thus be warranted in the acute setting, even if BAO is not
likely because outcome crucially depends on prompt diagnosis and successful recanalization without delays.3,5
CTA and magnetic resonance imaging (MRI) (including
standard nonenhanced, as well as angiographic sequences)
are acknowledged as reference standard noninvasive imaging modalities for BAO. Among these, CTA generally has a
higher availability, faster acquisition time, and lower costs,
but uses ionizing radiation and is especially associated with a
greater risk of contrast medium-induced complications. This
raises the question whether a more costly diagnostic technique
such as MRI is justified in all patients even if the diagnosis of
BAO is rather unlikely. Higher costs of CTA and MRI must
be weighed against the risk of false-negative results leading to
delayed diagnosis with NECT and DUS.
The aim of this study was to determine the cost effectiveness of different imaging strategies using NECT, DUS, CTA,
MRI, or combinations of these tests in patients with possible
BAO.
were contraindications for IV thrombolysis. The 1-month modified
rankin Scale (mRS) score was used to measure short-term outcome. A
Markov model with a 1-year cycle length was developed to estimate
long-term outcomes and costs. Further details about the decision
model are given in the online-only Data Supplement.
Data Sources and Input Parameters
The input data were based on the best available evidence in the literature. Clinical trial data and published clinical studies were used to
estimate the input parameters (Tables 1 and 2; Table I in the onlineonly Data Supplement.
Prior Probability
As BAO can present with an extremely broad spectrum of symptoms,
the prior probability may vary significantly depending on the clinical
symptoms at the time of presentation.6,10,11 We, therefore, assessed a
broad range of prior probabilities in deterministic and probabilistic
sensitivity analyses. Furthermore, as low prior probabilities are encountered mostly among patients with mild symptoms, we performed
a subgroup analysis for this patient group, thereby also accounting
for different outcomes among patients with different presentations.
The corresponding input parameters for our model are presented in
Table 1.
Diagnostic Test Performance
Data on the performance of NECT and DUS were derived from crosssectional studies that compared NECT9,10 and DUS8,11,27 to CTA as
reference standard. Differences in the assessment of DUS originated
from the application of contrast-enhanced techniques,11,27 which is
still experimental and probably not readily available in the emergency
department but promted us to perform extensive sensitivity analyses.
CTA and MR angiography are considered noninvasive standard
tests with a sensitivity and specificity of close to 1.0.14–16 Further detail about the diagnostic test performances is given in the online-only
Data Supplement. The corresponding test performances that served
as input parameters for our model are presented in Table 1.
Materials and Methods
Decision Model
We developed a decision model using decision-analytic software
(TreeAge Pro 2014, version 14.1.1.0; TreeAge, Williamstown,
MA) to evaluate the cost-effectiveness of different imaging strategies for the diagnostic work-up of possible BAO in 63-year-old men3
(Figure 1). We assessed NECT, CTA, and MRI separately, as well as
duplex US combined with CTA or MRI. MRI for the exclusion of
BAO both consists of unenhanced sequences to exclude an intracranial hemorrhage, as well as time-of-flight MR angiography. In the
combination strategies, CTA or MRI followed any abnormal duplex
US result. Treatment was initiated if the test result of NECT, CTA, or
MRI was positive. The time delay of treatment associated with each
strategy, as well as other advantages and disadvantages were modeled. Treatment was with IV thrombolysis or antithrombotics if there
Treatment Results
We modeled IV thrombolysis as treatment for BAO. As randomized
trials on the optimal treatment of BAO treatment are still underway,
there is currently no clear evidence for the superiority of endovascular treatment for IV thrombolysis.3,28,29 Thus, we modeled only IV
thrombolysis.
We derived the 1-month mRS outcomes for patients with
BAO depending on the type of treatment performed from a study
M
M
M
M
3
2
M
1
M
M
Figure 1. Schematic model overview. ☐, decision
node; ◯, chance node; M, Markov node; clone, the
structure of the tree at that point is identical to the
structure of a sub tree (marked with a thick black
line and a corresponding number) but the input
parameters are adjusted to apply to that specific
situation. MRI+MR angiography (MRA) and NECT
have a similar structure to computed tomographic
angiography (CTA). DUS followed by MRI+MRA
has a similar structure to DUS followed by CTA.
*Delayed treatment follows after reimaging but has
poorer long-term outcomes than immediate treatment. BAO indicates basilar artery occlusion; DUS,
duplex US; FN, false-negative; FP, false-positive;
IV, intravenous; MRI, magnetic resonance imaging;
NECT, nonenhanced CT; TN, true-negative; and TP,
true-positive.
1842 Stroke July 2015
Table 1. Summary of Input Parameters for the Decision Model With SE and Distribution Type, as well as References
Model Parameter
Expected Value
SE
Distribution
References
Age
63
±10%
Normal
Schonewille et al3
Pretest probability
0.3
0.01–0.5
Uniform
Estimated from the study by Goldmakher et al10 and
Kermer et al11
NECT sensitivity
0.66
±10%
β
Connell et al9 and Goldmakher et al10
NECT specificity
0.85
±10%
β
Connell et al9 and Goldmakher et al10
DUS sensitivity
0.95
0.89–1.0
Triangular
Brandt et al,8 Stolz et al,12 and Hoksbergen et al13
DUS specificity
0.70
0.5–0.9
Triangular
Brandt et al,8 Stolz et al,12 and Hoksbergen et al13
CTA sensitivity
1.00
0.99–1.0
Triangular
Ng et al14 and Bonatti et al15
CTA specificity
1.00
0.99–1.0
Triangular
Ng et al14 and Bonatti et al15
MRI sensitivity
1.00
0.99–1.0
Triangular
Wentz et al16
MRI specificity
1.00
0.99–1.0
Triangular
Wentz et al16
mRS, 0–2
0.29
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 3–5
0.35
±20%
β
Schonewille et al3 and Vergouwen et al5
Death
0.36
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 0–2
0.26
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 3–5
0.36
±20%
β
Schonewille et al3 and Vergouwen et al5
Death
0.38
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 0–2
0.11
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 3–5
0.50
±20%
β
Schonewille et al3 and Vergouwen et al5
Death
0.39
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 0–2
0.09
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 3–5
0.45
±20%
β
Schonewille et al3 and Vergouwen et al5
Death
0.46
±20%
β
Schonewille et al3 and Vergouwen et al5
mRS, 0–2
0.35
±20%
β
Schonewille et al3
mRS, 3–5
0.38
±20%
β
Schonewille et al3
Death
0.27
±20%
β
Schonewille et al3
mRS, 0–2
0.31
±20%
β
Schonewille et al3
mRS, 3–5
0.39
±20%
β
Schonewille et al3
Death
0.30
±20%
β
Schonewille et al3
mRS, 0–2
0.14
±20%
β
Schonewille et al3
mRS, 3–5
0.56
±20%
β
Schonewille et al3
Death
0.30
±20%
β
Schonewille et al3
mRS, 0–2
0.12
±20%
β
Schonewille et al3
mRS, 3–5
0.51
±20%
β
Schonewille et al3
Death
0.37
±20%
β
Schonewille et al3
Healthy
1
…
…
Assumption
Death
0
…
…
Assumption
Test performances
Outcome probabilities
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BAO, thrombolysis 0–3 h
BAO, thrombolysis 4–6 h
BAO, thrombolysis 7–9 h
BAO, thrombolysis >9 h
BAO, antithrombotics 0–3 h
BAO, antithrombotics 4–6 h
BAO, antithrombotics 7 to 9 h
BAO, antithrombotics > 9 h
No BAO
(Continued )
Beyer et al Basilar Artery Occlusion Cost-Effect Analysis 1843
Table 1. Continued
Model Parameter
Expected Value
SE
Distribution
References
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Timing data, min
Time from symptom onset
312
±240
γ
Vergouwen et al5
Perform and interpret NECT
10
5–15
Triangular
Expert opinion
Perform and interpret CTA
15
10–20
Triangular
Expert opinion
Perform and interpret MRI
45
20–60
Triangular
Earnshaw et al17
Perform and interpret DUS
30
20–50
Triangular
Expert opinion
Delay if false-negative
180
10–360
Uniform
Expert opinion
Utility values
Healthy
1
…
…
…
mRS, 0–2
0.81
±0.081
β
Earnshaw et al,17 Stahl et al,18 and Gage et al19
mRS, 3–5
0.33
±0.033
β
Earnshaw et al,17 Stahl et al,18 and Gage et al19
Death
0
…
…
…
Death HRR
mRS, 0–1
1.00
1.0–1.2
Triangular
Earnshaw et al17 and Samsa et al20
mRS, 2
1.11
1.0–1.2
Triangular
Earnshaw et al17 and Samsa et al20
mRS, 3
1.27
1.2–1.4
Triangular
Earnshaw et al17 and Samsa et al20
mRS, 4
1.71
1.3–2.0
Triangular
Earnshaw et al17 and Samsa et al20
mRS, 5
2.37
1.5–4.0
Triangular
Earnshaw et al17 and Samsa et al20
Complication probabilities
Contrast-induced nephropathy
0.005
0–0.02
Triangular
Jackson et al21
Contraindications for IV
0.05
±20%
β
Katzan et al22
thrombolysis
Lifetime attributable risk of cancer
0.0001
±0.00001
Normal
Holmes et al23
after NECT scanning
Lifetime attributable risk of cancer
0.0002
±0.00002
Normal
Holmes et al23
after CTA scanning
BAO indicates basilar artery occlusion; CTA, computed tomographic angiography; DUS, duplex ultrasound; HRR, hazard rate ratios; MRI, magnetic
resonance imaging; mRs, modified rankin Scale; and NECT, nonenhanced computed tomography.
by Vergouwen et al5 investigating the data of the Basilar Artery
International Cooperation Study (BASICS), a large prospective registry study.3 These outcomes were similar to previously published
90-days outcomes after IV thrombolysis4 but allowed a separate
evaluation of patients receiving thrombolytic and patients receiving
antithrombotic therapy as well as analysis of prognostic factors, such
as time from symptom onset to treatment.
On the basis of a study by Katzan et al,22 we estimated that 5%
of patients with BAO would have contraindications for thrombolytic
therapy (ie, active gastro intestinal tract bleeding, uncontrolled hypertension, oral anticoagulation with international normalized ratio >1.7,
or recent brain injury). This number is considerably lower than the
total number of ineligible patients in their study because (1) in BAO
there is no clear time window for the administration of thrombolytic
therapy and (2) contraindications, such as minor symptoms (National
Institutes of Health Stroke Scale <4) and rapidly resolving symptoms
would not apply for patients with BAO.
The BASICS study evaluated outcomes separately for patients
with mild-to-moderate and severe symptoms.3 In our model, we performed an overall analysis using the pooled data from these 2 groups,
as well as a subgroup analysis for patients with mild symptoms. The
corresponding input parameters for the overall analysis and for the
subgroup analysis for patients with mild symptoms are presented in
Table 1 and in Table I in the online-only Data Supplement, respectively.
Age- and sex-specific live tables were obtained for the US population of 2007. The hazard rate ratios for the different health states
(mRS, 0–5) were derived from the literature.17,20
onset as a factor determining the outcome after initiation of treatment.
Detailed information is available in the online-only Data Supplement.
For each imaging strategy, a corresponding delay was added to
the time from symptom onset. The respective input parameters are
presented in Table 1.
Timing to Treatment
Costs
Time from symptom onset predicts the success of thrombolytic therapy in the anterior circulation30 and influences the treatment outcome in
patients with BAO.5,31 Consequently, we modeled time from symptom
The model included costs for imaging with NECT, DUS, CTA, and
MRI, complications from imaging, treatment with IV thrombolysis,
and disability from BAO, including both short- and long-term care.
Adverse Events
Information on the adverse events was obtained from the literature.21,23,32,33 We modeled contrast-induced nephropathy because of
administration of contrast media during CTA21and risk of fatal radiation-induced cancer because of CT scanning.23,32 The respective input
parameters are given in Table 1. Detailed information is available in
the online-only Data Supplement.
Health Benefit
Health benefits were measured using quality-adjusted life years
(QALY). Lifetime QALYs were derived by multiplication of the number of years spent in each health state by the utility assigned to that
health state. Utility weights range from 0.0 to 1.0, with 1.0 representing
perfect health and 0.0 representing death. The utilities were obtained
from 2 previously published studies,18,19 which have been used repeatedly in prior cost-effectiveness analyses.17,34 The utilities were calculated
as averages weighted by the proportions of patients with the respective
mRS outcome. The utility of a minor disability (mRS, 0–2) was 0.81
and the utility of a major disability (mRS, 3–5) was 0.33. Death (mRS,
6) was assigned a value of 0. The values are summarized in Table 1.
1844 Stroke July 2015
Table 2. Costs in 2013 USD for Imaging, Complications From Imaging, Treatment and Disability
From BAO, Including Both Short- and Long-Term Care
Model Parameter
Expected Value
SE
Distribution
References
NECT
167
±16.7
γ
Medicare 2013
DUS
211
±21.1
γ
Medicare 2013
CTA+NECT
424
±42.4
γ
Medicare 2013
MRI+MRA
804
±80.4
γ
Medicare 2013
IV tPA
3829.55
±382.96
γ
Earnshaw et al17
Administration of IV tPA
354.30
±35.43
γ
Earnshaw et al17
Physician time to monitor IV tPA
administration
711.97
±71.20
γ
Earnshaw et al17
9809
4200–16 800
Triangular
Young et al24
Annual post hospitalization costs for
patients with mRS 0–2
8174
1–17 500
Triangular
Young et al24
Annual post hospitalization costs for
patients with mRS, 3–5, first year
68 897
46 700–93 500
Triangular
Young et al24
Annual post hospitalization costs for
patients with mRS 3–5, 2+ year
40 014
17 500–64 300
Triangular
Young et al24
Cost for contrast induced nephropathy
13 323
±1332
γ
Jackson et al21
Cost for cancer
45 000
1–100 000
Triangular
Estimated from23,25,26
Imaging
Treatment
Hospitalization
Inpatient costs for patients with BAO
Post-hospitalization
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Complications
BAO indicates basilar artery occlusion; CTA, computed tomographic angiography; DUS, duplex ultrasound; IV, intravenous;
MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; mRs, modified rankin Scale; NECT, nonenhanced
computed tomography; and tPA, tissue-type plasminogen activator.
Costs for imaging were based on the 2013 Medicare reimbursement rates, including both technical and professional fees. Costs for
complications from imaging have been described above. Costs for
hospitalization have been reported in the literature.24 These costs
included all costs incurred while in a hospital and total costs were
obtained by stroke type and discharge status. The costs for treatment
with IV thrombolysis were obtained from Earnshaw et al.17 Costs for
IV thrombolysis included physician work and practice expense.
Annual post hospitalization costs have been repeatedly reported in
the literature.17,24,35,36 These costs were obtained based on the patient’s
health state. Death (mRS, 6) was assigned no annual post hospitalization cost. All costs were converted into 2013 USD using the consumer
price index for medical care. Benefits and costs were discounted at a
rate of 3% per year as recommended for cost-effectiveness analyses
in the United States.37 A summary of all costs used in this model is
presented in Table 2.
Cost-Effectiveness and Sensitivity Analyses
Diagnostic strategies were compared in terms of costs, effectiveness
(QALYs), incremental cost-effectiveness ratios, and net monetary
benefit (NMB=QALY×willingness-to-pay [WTP]−costs), using a
WTP threshold of $80 000 per QALY. NMB combines costs and effectiveness in 1 measure (NMB=(QALYs×WTP)−costs) with a higher NMB implying greater cost-effectiveness. QALYs and costs were
calculated from the perspective of a healthcare payer.
We performed extensive sensitivity analyses to explore the robustness of the model’s assumptions. We used 1-way deterministic
sensitivity analysis to identify variables with a significant influence
on the model outcome. In addition, we performed 2- and 3-way sensitivity analyses by altering the input values for 2 and 3 variables,
respectively. A WTP threshold of $80,000 was used for these sensitivity analyses.
In addition to deterministic sensitivity analysis, we also performed probabilistic sensitivity analyses, in which we altered the
input values of all parameters simultaneously. Each parameter was
assigned a distribution (β, triangular, or γ) and was varied according
to this distribution. In addition, we calculated the probability of costeffectiveness for each strategy for varying WTP values using acceptability curves.
Results
Reference Case Analysis
In the reference-case analysis for male patients of 63 years
old with possible BAO, CTA dominated all other strategies
(Figure 2A). With a WTP threshold of $80 000 per QALY,
CTA yielded the highest NMB, followed by MRI. The least
cost-effective strategy was to perform NECT. In the reference-case analysis for patients with mild symptoms, CTA also
dominated all other strategies (Figure 2C), albeit with smaller
differences in QALYs and total costs compared with the overall analysis. A summary of the results is presented in Table 3.
The results were similar for women (Table II; Figure I in the
online-only Data Supplement).
Probabilistic Sensitivity Analysis
Results of the probabilistic sensitivity analysis showed that in
men CTA was most cost effective in 96% of the simulation runs
in the overall analysis and 80% of the mild symptoms analysis.
DUS followed by CTA and DUS followed by MRI were the
strategies of choice in only 2.6% and 0.07% of simulation runs
Beyer et al Basilar Artery Occlusion Cost-Effect Analysis 1845
in the overall analysis and 13% and 4.1% of simulation runs in
the mild symptoms analysis, respectively. Those results were
similar for women. The cost-effectiveness acceptability curves
showing the most cost-effective strategy depending on the WTP
threshold are given in Figure 2B and 2C for men and in Figure
IB and IC in the online-only Data Supplement for women.
Deterministic Sensitivity Analyses
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Prior Probability and Age
The model outcome was sensitive to varying the prior probability. With a WTP threshold of $80,000/QALY, CTA was
more effective with an incremental cost-effectiveness ratio
below the WTP threshold if the prior probability was >0.018
for the overall analysis or >0.024 for patients with mild symptoms. With prior probabilities less than 0.018 and 0.024, DUS
followed by CTA was more cost effective.
Model outcome was also influenced by the age of the
patient. Varying age together with the prior probability in
2-way sensitivity analyses showed that at a younger age <40
years the MRI strategy was increasingly favored, whereas
at age ≥80 years DUS followed by CTA was increasingly
favored, at least in patients with a low prior probability.
However, changes were minimal between the age of 45 and
80 years—the age group, in which the vast majority of BAO
cases occur (Figure II in the online-only Data Supplement).
DUS Sensitivity and Specificity
The choice between CTA and DUS followed by CTA was also
affected by the sensitivity and specificity of DUS. Altering
these 2 parameters together with the prior probability in 3-way
sensitivity analyses showed that DUS followed by CTA would
be cost-effective also at higher prior probabilities if sensitivity and specificity increased. However, even with perfect sensitivity and specificity, the prior probabilities at which DUS
followed by CTA was cost effective were low. Above a prior
probability of ≈0.04 CTA was always the most cost-effective
strategy (Figure 3 for men and Figure III in the online-only
Data Supplement for women). In contrast, there was no
change in cost-effectiveness if the sensitivity of CTA was varied between 0.95 and 1.0 together with the prior probability.
Varying the specificity of CTA between 0.95 and 1.0 resulted
in slight changes of the cost-effectiveness between prior probabilities of 0.02 and 0.03 for both analyses, favoring DUS
followed by CTA also for higher probabilities if the specificity of CTA decreased. Varying the sensitivity or specificity of
MRI between 0.95 and 1.0 did not result in any changes of the
model outcome.
Radiation Risk
Figure IV in the online-only Data Supplement shows the
2-way sensitivity analyses exploring the influence of the
lifetime attributable risk of cancer because of CT scanning.
A
B
C
D
Figure 2. Cost-effectiveness graphs and acceptability curves in male patients. A and B, The results of the overall analysis. C and D,
The results of the mild symptoms subgroup analysis. Cost-effectiveness graphs are shown in (A) and (C), acceptability curves are shown
in (B) and (D). CTA is the optimal strategy in the overall analysis (A and B) and for patients with mild symptoms (C and D). CTA indicates
computed tomographic angiography; DUS, duplex US; MRI, unenhanced magnetic resonance sequences+magnetic resonance angiography; NECT, nonenhanced CT; and QALY, quality-adjusted life-year.
1846 Stroke July 2015
Varying the lifetime attributable risk (LAR) after a single CT
scan between 0 and 0.0003, the upper value corresponding to
3× the estimated risk, resulted in a change of the most costeffective strategy between prior probabilities of 0.01 and 0.04,
favoring DUS followed by CTA, as well as MRI as the LAR
increased. Above a prior probability of 0.04, CTA was the
most cost-effective strategy. There was only a marginal difference between the overall analysis and the analysis of patients
with mild symptoms.
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Timing to Treatment
Performing deterministic 2-way sensitivity analysis on the time
to image and interpret MRI did not result in a change of the
most cost-effective strategy at any prior probability in the overall analysis or in the analysis of patients with mild symptoms.
Nor did performing sensitivity analysis on the time to image
and interpret CTA result in a change of the most cost-effective
strategy because both CTA as well as DUS followed by CTA
were influenced by this analysis. Longer times to perform DUS
resulted in changes of the most cost-effective strategy around
a prior probability of 0.02, favoring direct CTA also in case
of lower prior probabilities because the time to perform DUS
increased (Figure V in the online-only Data Supplement).
Discussion
In our study on the cost-effectiveness of different noninvasive imaging tests for patients with possible BAO, we found
direct CTA to be the most cost-effective strategy for a WTP
threshold of $80 000/QALY. CTA yielded the most QALYs
and although CTA was associated with higher initial imaging costs, total costs were lower compared with other imaging strategies as costs for long-term treatment were less. It,
therefore, represented a dominant strategy. Cost-effectiveness
acceptability curves showed that CTA remained cost-effective
even for higher WTP thresholds.
Sensitivity analysis showed that DUS followed by CTA
in case of a positive test result is cost effective for low prior
Table 3. Costs and Outcomes for Men
Total Costs
(USD)
QALYs
ICER
NMB for WTP of $80 000/
QALY
Overall
CTA
70 996
15.20
Dominant
1 144 992
DUS+CTA
71 678
15.16
Dominated
1 141 130
DUS+MRI
72 295
15.13
Dominated
1 138 455
MRI
71 701
15.18
Dominated
1 142 496
NECT
72 438
15.14
Dominated
1 138 415
Mild symptoms
CTA
31 759
17.59
Dominant
1 375 338
DUS+CTA
31 785
17.58
Dominated
1 374 339
DUS+MRI
31 989
17.57
Dominated
1 374 484
MRI
32 102
17.58
Dominated
1 374 498
NECT
32 351
17.57
Dominated
1 373 187
CTA indicates computed tomographic angiography; ICER, incremental costeffectiveness ratio; MRI, magnetic resonance imaging; NECT, nonenhanced
computed tomography; NMB, net monetary benefit; QALY, quality-adjusted lifeyear; and WTP, willingness-to-pay.
probabilities. Depending on the sensitivity and specificity of
DUS, the cut-off value of the prior probability below which
DUS followed by CTA became the preferred strategy, varied between 1% and 4%. Notably, even if perfect sensitivity and specificity were assumed, which would also require
DUS to always yield interpretable results, CTA was still the
most cost-effective strategy for prior probabilities above
4%. Considering more realistic values for an acute setting,
in which DUS may be uninterpretable in ≤50% when using
noncontrast enhanced techniques,8 performing DUS because
the initial test may only be cost-effective if the prior probability is <1%. These results remained nearly unchanged
for females and for patients with mild symptoms at initial
presentation.
Our results emphasize the paramount importance of a
fast diagnostic work-up in BAO, also in relation to the cost
of the imaging examination or potential risks, such as renal
nephropathy or radiation-induced cancer. In our model, the
delay was the key driver determining the most cost-effective
strategy. It was the reason why performing DUS was only
cost-effective at low prior probabilities—in combination
with higher costs—why MRI never became the preferred
strategy. Although there is no data available on the prior
probability of BAO in patients only exhibiting mild symptoms to date, clinical experience indicates that the probability may be ≥1%.
There are limitations of this study that need to be taken
into account when interpreting the data. Because of limited
evidence in the literature, several assumptions had to be made.
First, as BAO is a rare disease, which can present with a vast
variety of clinical symptoms,3,6 it is difficult to estimate the
prior probability. This may question the generalizability of
this model. Sensitivity analyses, however, showed that CTA
remained cost-effective for most prior probabilities, whereas
DUS became cost-effective only at low prior probabilities of
around 1% to 2%. This indicates that CTA is cost-effective
for many patients but implementation of the results of this
study should be done cautiously for patients in whom BAO is
unlikely. Our findings may thus work as a framework to help
the physician in the initial decision-making process.
Second, the performance of imaging tests has only
been described in studies with small numbers of patients.8,9
Especially for DUS there is only limited data available.
Sensitivity analysis, however, showed that the outcomes were
robust to changes of these input parameters and that CTA was
the most cost-effective strategy in the vast majority of scenarios tested. The outcome between DUS and CTA was mainly
driven by the effect of the time to perform and interpret test
results and thus alterations of the values of test performance
of DUS only resulted in slight changes in cost-effectiveness at
prior probabilities between 1% and 4%.
Third, the predicted cancer risk associated with cranial
CT scanning was derived from a study23 that used extrapolation of risks of cancers found in a meta-analysis for pediatric patients.38 In general, there is still uncertainty about the
risk attributable to cranial CT scanning. Current estimates
commonly use organ radiation doses and apply organ-specific cancer incidences, which are derived from studies of
Beyer et al Basilar Artery Occlusion Cost-Effect Analysis 1847
A
B
C
D
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Figure 3. Three-way sensitivity analyses exploring different sensitivities and specificities of duplex US (DUS) and different prior probabilities with a willingness-to-pay of $80 000 per quality-adjusted life-year in men. A and B, The results of the overall analysis. C and D ,
The results of the mild symptoms subgroup analysis. Shading, optimal strategy. CTA indicates computed tomographic angiography; MRI,
nonenhanced magnetic resonance sequences+magnetic resonance angiography; and NECT, nonenhanced CT.
atomic-bomb survivors.39 The LAR of 0.0001 used in our
study was derived from Holmes et al.23 who extrapolated
the higher risks found for patients between the ages 0 and
20 years by Stein et al.38 The estimates of Stein et al are in
line with earlier reports.40 Nevertheless, there is still ambiguity about the LAR for adult patients we used in our study.
However, sensitivity analyses showed that even an LAR 2×
higher than the estimate only slightly influenced the model
outcome, therefore, indicating only a minor role in the decision process for the diagnostic work-up of such a fatal disease, such as BAO.
Fourth, we only modeled IV thrombolysis as outcome,
omitting potential intra-arterial treatment options. Therefore,
we are not able to extrapolate the results to strategies guiding those treatment options. The rationale was that this study
intended to focus on the initial diagnostic imaging work-up
by highlighting the influence of potential advantages and
disadvantages associated with each of the different imaging
strategies. Therefore, it was necessary to use the best evidence on outcome estimates available to date. This is provided by the BASICS study.3 Because this study did not find
any significant differences in the outcome between IV and
IA thrombolysis, we limited the treatment in our model to
IV therapy. It should be noted that our findings were robust,
remaining nearly unchanged independent of whether outcome estimates for all patients or for patients with mild
symptoms were used, thereby indicating that better outcomes
achieved with intra-arterial therapy may not change the decision of the initial imaging strategy. However, direct catheter
angiography with the opportunity for an immediate intervention may become cost-effective if the prior probability
is high. Currently, a randomized controlled trial is being
performed investigating the added value of IA therapy after
IV therapy in patients with an acute symptomatic BAO.41 As
soon as these data become available, our model can be easily
adapted and updated.
Finally, the model assumed that CT, MRI, and DUS are
available 24 hours a day, 7 days a week. Such an assumption may only be valid for a stroke center and not for a
small, rural hospital. However, as CT-based imaging is still
the recommended standard for acute stroke work-up, CTA
as the most cost-effective strategy in our model is likely to
be available more readily than MRI or DUS. Furthermore,
the model assumed that CT and MRI always yield interpretable results. This is in fact an oversimplified assumption
because CT may be uninterpretable, for example, because
of beam-hardening artifacts8 and MRI, for example, because
of motion artifacts. We chose to refrain from modeling this
because there is uncertainty about the risk of scans being
uninterpretable. Sensitivity analyses, however, showed that
results remained nearly unchanged even if CTA sensitivity
and specificity were altered between 0.95 and 1.0, which
may be used as an indicator of limited influence of uninterpretable test results.
1848 Stroke July 2015
In conclusion, we demonstrated CTA to be cost-effective
as the initial imaging test in many patients with possible BAO
in an US American setting. When using standard noncontrast
enhanced DUS techniques, DUS followed by CTA in case of
an abnormal result is only cost-effective if the prior probability is less than ≈1%. NECT and MRI are not cost-effective for
this indication.
Disclosures
None.
References
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
1. Ottomeyer C, Zeller J, Fesl G, Holtmannspötter M, Opherk C, Bender A,
et al. Multimodal recanalization therapy in acute basilar artery occlusion:
long-term functional outcome and quality of life. Stroke. 2012;43:2130–
2135. doi: 10.1161/STROKEAHA.112.651281.
2. Baird TA, Muir KW, Bone I. Basilar artery occlusion. Neurocrit Care.
2004;1:319–329. doi: 10.1385/NCC:1:3:319.
3. Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle
HP, et al; BASICS study group. Treatment and outcomes of acute basilar
artery occlusion in the Basilar Artery International Cooperation Study
(BASICS): a prospective registry study. Lancet Neurol. 2009;8:724–730.
doi: 10.1016/S1474-4422(09)70173-5.
4. Sairanen T, Strbian D, Soinne L, Silvennoinen H, Salonen O, Artto
V, et al; Helsinki Stroke Thrombolysis Registry (HSTR) Group.
Intravenous thrombolysis of basilar artery occlusion: predictors of
recanalization and outcome. Stroke. 2011;42:2175–2179. doi: 10.1161/
STROKEAHA.110.605584.
5.Vergouwen MD, Algra A, Pfefferkorn T, Weimar C, Rueckert CM,
Thijs V, et al; Basilar Artery International Cooperation Study (BASICS)
Study Group. Time is brain(stem) in basilar artery occlusion. Stroke.
2012;43:3003–3006. doi: 10.1161/STROKEAHA.112.666867.
6. von Campe G, Regli F, Bogousslavsky J. Heralding manifestations of
basilar artery occlusion with lethal or severe stroke. J Neurol Neurosurg
Psychiatry. 2003;74:1621–1626.
7. Mortimer AM, Saunders T, Cook JL. Cross-sectional imaging for diagnosis and clinical outcome prediction of acute basilar artery thrombosis.
Clin Radiol. 2011;66:551–558. doi: 10.1016/j.crad.2010.09.022.
8. Brandt T, Knauth M, Wildermuth S, Winter R, von Kummer R, Sartor
K, et al. CT angiography and Doppler sonography for emergency assessment in acute basilar artery ischemia. Stroke. 1999;30:606–612.
9. Connell L, Koerte IK, Laubender RP, Morhard D, Linn J, Becker HC, et al.
Hyperdense basilar artery sign-a reliable sign of basilar artery occlusion.
Neuroradiology. 2012;54:321–327. doi: 10.1007/s00234-011-0887-6.
10. Goldmakher GV, Camargo EC, Furie KL, Singhal AB, Roccatagliata L,
Halpern EF, et al. Hyperdense basilar artery sign on unenhanced CT predicts thrombus and outcome in acute posterior circulation stroke. Stroke.
2009;40:134–139. doi: 10.1161/STROKEAHA.108.516690.
11.Kermer P, Wellmer A, Crome O, Mohr A, Knauth M, Bähr M.
Transcranial color-coded duplex sonography in suspected acute basilar artery occlusion. Ultrasound Med Biol. 2006;32:315–320. doi:
10.1016/j.ultrasmedbio.2005.12.004.
12. Stolz E, Nückel M, Mendes I, Gerriets T, Kaps M. Vertebrobasilar transcranial color-coded duplex ultrasonography: improvement with echo
enhancement. AJNR Am J Neuroradiol. 2002;23:1051–1054.
13. Hoksbergen AW, Legemate DA, Ubbink DT, Jacobs MJ. Success rate
of transcranial color-coded duplex ultrasonography in visualizing the
basal cerebral arteries in vascular patients over 60 years of age. Stroke.
1999;30:1450–1455.
14. Ng KW, Venketasubramanian N, Yeo LL, Ahmad A, Loh PK, Seet
RC, et al. Usefulness of CT angiography for therapeutic decision making in thrombolyzing intubated patients with suspected
basilar artery thrombosis. J Neuroimaging. 2012;22:351–354. doi:
10.1111/j.1552-6569.2011.00689.x.
15. Bonatti G, Ferro F, Haglmüller T, Pernter P, Naibo L. Basilar artery thrombosis: imaging and endovascular therapy. Radiol Med. 2010;115:1219–
1233. doi: 10.1007/s11547-010-0568-2.
16. Wentz KU, Röther J, Schwartz A, Mattle HP, Suchalla R, Edelman
RR. Intracranial vertebrobasilar system: MR angiography. Radiology.
1994;190:105–110. doi: 10.1148/radiology.190.1.8259384.
17.Earnshaw SR, Jackson D, Farkouh R, Schwamm L. Costeffectiveness of patient selection using penumbral-based MRI for
intravenous thrombolysis. Stroke. 2009;40:1710–1720. doi: 10.1161/
STROKEAHA.108.540138.
18. Stahl JE, Furie KL, Gleason S, Gazelle GS. Stroke: Effect of implementing an evaluation and treatment protocol compliant with NINDS
recommendations. Radiology. 2003;228:659–668. doi: 10.1148/
radiol.2283021557.
19. Gage BF, Cardinalli AB, Owens DK. Cost-effectiveness of preferencebased antithrombotic therapy for patients with nonvalvular atrial fibrillation. Stroke. 1998;29:1083–1091.
20.Samsa GP, Reutter RA, Parmigiani G, Ancukiewicz M, Abrahamse
P, Lipscomb J, et al. Performing cost-effectiveness analysis by integrating randomized trial data with a comprehensive decision model:
application to treatment of acute ischemic stroke. J Clin Epidemiol.
1999;52:259–271.
21. Jackson D, Earnshaw SR, Farkouh R, Schwamm L. Cost-effectiveness
of CT perfusion for selecting patients for intravenous thrombolysis: a US
hospital perspective. AJNR Am J Neuroradiol. 2010;31:1669–1674. doi:
10.3174/ajnr.A2138.
22. Katzan IL, Hammer MD, Hixson ED, Furlan AJ, Abou-Chebl A, Nadzam
DM; Cleveland Clinic Health System Stroke Quality Improvement
Team. Utilization of intravenous tissue plasminogen activator for
acute ischemic stroke. Arch Neurol. 2004;61:346–350. doi: 10.1001/
archneur.61.3.346.
23.Holmes MW, Goodacre S, Stevenson MD, Pandor A, Pickering A.
The cost-effectiveness of diagnostic management strategies for adults
with minor head injury. Injury. 2012;43:1423–1431. doi: 10.1016/j.
injury.2011.07.017.
24. Young KC, Benesch CG, Jahromi BS. Cost-effectiveness of multimodal
CT for evaluating acute stroke. Neurology. 2010;75:1678–1685. doi:
10.1212/WNL.0b013e3181fc2838.
25. Lester SC, Taksler GB, Kuremsky JG, Lucas JT Jr, Ayala-Peacock DN,
Randolph DM II, et al. Clinical and economic outcomes of patients
with brain metastases based on symptoms: an argument for routine
brain screening of those treated with upfront radiosurgery. Cancer.
2014;120:433–441. doi: 10.1002/cncr.28422.
26.Ray S, Bonafede MM, Mohile NA. Treatment Patterns, Survival,
and Healthcare Costs of Patients with Malignant Gliomas in a Large
US Commercially Insured Population. Am Health Drug Benefits.
2014;7:140–149.
27. Koga M, Kimura K, Minematsu K, Yamaguchi T. Relationship between
findings of conventional and contrast-enhanced transcranial color-coded
real-time sonography and angiography in patients with basilar artery
occlusion. AJNR Am J Neuroradiol. 2002;23:568–571.
28. Mattle HP, Arnold M, Lindsberg PJ, Schonewille WJ, Schroth G. Basilar
artery occlusion. Lancet Neurol. 2011;10:1002–1014. doi: 10.1016/
S1474-4422(11)70229-0.
29. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis.
Stroke. 2006;37:922–928. doi: 10.1161/01.STR.0000202582.29510.6b.
30. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al;
ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group. Time to
treatment with intravenous alteplase and outcome in stroke: an updated
pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.
Lancet. 2010;375:1695–1703. doi: 10.1016/S0140-6736(10)60491-6.
31. Greving JP, Schonewille WJ, Wijman CA, Michel P, Kappelle LJ, Algra
A; BASICS Study Group. Predicting outcome after acute basilar artery
occlusion based on admission characteristics. Neurology. 2012;78:1058–
1063. doi: 10.1212/WNL.0b013e31824e8f40.
32. Genders TS, Meijboom WB, Meijs MF, Schuijf JD, Mollet NR, Weustink
AC, et al. CT coronary angiography in patients suspected of having coronary
artery disease: decision making from various perspectives in the face of uncertainty. Radiology. 2009;253:734–744. doi: 10.1148/radiol.2533090507.
33. Ottomeyer C, Sick C, Hennerici MG, Szabo K. Orolingual angioedema
under systemic thrombolysis with rt-PA: an underestimated side effect.
Nervenarzt. 2009;80:459–463. doi: 10.1007/s00115-009-2685-5.
34. Boudreau DM, Guzauskas GF, Chen E, Lalla D, Tayama D, Fagan SC,
et al. Cost-effectiveness of recombinant tissue-type plasminogen activator within 3 hours of acute ischemic stroke: current evidence. Stroke.
2014;45:3032–3039. doi: 10.1161/STROKEAHA.114.005852.
35. Post PN, Kievit J, van Baalen JM, van den Hout WB, van Bockel
JH. Routine duplex surveillance does not improve the outcome after
carotid endarterectomy: a decision and cost utility analysis. Stroke.
2002;33:749–755.
Beyer et al Basilar Artery Occlusion Cost-Effect Analysis 1849
36. Kilaru S, Korn P, Kasirajan K, Lee TY, Beavers FP, Lyon RT, et al.
Is carotid angioplasty and stenting more cost effective than carotid
endarterectomy? J Vasc Surg. 2003;37:331–339. doi: 10.1067/
mva.2003.124.
37.Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB.
Recommendations of the Panel on Cost-effectiveness in Health and
Medicine. JAMA. 1996;276:1253–1258.
38. Stein SC, Hurst RW, Sonnad SS. Meta-analysis of cranial CT scans in
children. A mathematical model to predict radiation-induced tumors.
Pediatr Neurosurg. 2008;44:448–457. doi: 10.1159/000172967.
39. Brenner DJ, Hall EJ. Computed tomography–an increasing source of radiation
exposure. N Engl J Med. 2007;357:2277–2284. doi: 10.1056/NEJMra072149.
40. Brenner D, Elliston C, Hall E, Berdon W. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR Am J Roentgenol.
2001;176:289–296. doi: 10.2214/ajr.176.2.1760289.
41. van der Hoeven EJ, Schonewille WJ, Vos JA, Algra A, Audebert
HJ, Berge E, et al; BASICS Study Group. The Basilar Artery
International Cooperation Study (BASICS): study protocol
for a randomised controlled trial. Trials. 2013;14:200. doi:
10.1186/1745-6215-14-200.
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Different Imaging Strategies in Patients With Possible Basilar Artery Occlusion:
Cost-Effectiveness Analysis
Sebastian E. Beyer, Myriam G. Hunink, Florian Schöberl, Louisa von Baumgarten, Steffen E.
Petersen, Martin Dichgans, Hendrik Janssen, Birgit Ertl-Wagner, Maximilian F. Reiser and
Wieland H. Sommer
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Stroke. 2015;46:1840-1849; originally published online May 28, 2015;
doi: 10.1161/STROKEAHA.115.008841
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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SUPPLEMENTAL MATERIAL
Different Imaging Strategies in Patients with Possible Basilar Artery Occlusion:
a Cost-Effectiveness Analysis
SUPPLEMENTAL MATERIAL AND METHODS
Decision Model Overview
We developed a decision model using decision-analytical software (TreeAge Pro 2014,
version 14.1.1.0; TreeAge, Williamstown, Mass) to evaluate the cost-effectiveness of
different imaging strategies for the diagnostic work-up of possible BAO in 63-year old men 1
(Figure 1). The following strategies were considered: (i) CTA, (ii) MRI, (iii) NECT, (iv)
trans-cranial DUS followed by CTA in case of an abnormal result, and (v) trans-cranial DUS
followed by MRI in case of an abnormal result.
Modelling different imaging strategies
In order to exclude intra-cranial hemorrhage, NECT preceded CTA. MRI consisted of both
standard non-enhanced sequences, as well as MR angiography. If the test result of NECT,
CTA or MRI was positive, administration of IV thrombolysis followed. Even though IV
thrombolysis can sometimes be administered in stroke patients within the 4.5h time window
after a negative NECT ruling out intra-cranial hemorrhage, our model required a positive
result on NECT, CTA, or MRI since BAO may have a much lower prior probability and may
be treated well beyond the 4.5h time window. Because of this more specific treatment strategy
less treatment costs are incurred and more patients are eligible for therapy. If the patient had
contraindications for IV thrombolysis, antithrombotic therapy followed instead. If the test
result was negative, no anti-ischemic treatment (including antithrombotic or thrombolytic
therapy and heparin) was administered. Patients with a false-negative test result were reexamined after a time delay as they were expected to deteriorate. Re-evaluation was
performed using CTA after initial NECT or MRI false-negative results and MRI after an
initial CTA false-negative result. Re-evaluation was assumed to be diagnostic in all initially
false-negative cases but the time delay led to poorer long-term outcomes.
As transcranial doppler and color-coded duplex sonography are both user-dependent and
results indicative for BAO vary from absence of signal to abnormal wave forms 2-5, diagnostic
results were considered to be either (i) normal or (ii) abnormal. The rationale is that CTA or
MRI would follow any abnormal result. Thus, in this model ‘abnormal’ also includes uninterpretable test results. If DUS yielded an abnormal test result, CTA or MRI followed. In
case of false negative (i.e. false normal) result, CTA or MRI followed after a time delay as
those patients were expected to deteriorate.
The model assumed that all imaging modalities would be available for 24 hours a day for 7
days a week.
Modelling treatment effect and outcomes
We modeled IV thrombolysis as the standard treatment for BAO as there is currently an
ongoing debate whether endovascular treatment strategies including IA thrombolysis and
mechanical thrombectomy are indeed superior to IV thromboysis alone 6 with no high-class
evidence supporting one strategy 1, 7. Short-term outcomes were modeled with the decision
tree. Long-term outcomes were modeled with a Markov model with a cycle length of one
year. The Markov model simulated length and quality of life depending on whether or not
BAO was present and whether or not treatment was initiated. To measure outcome, the onemonth modified ranking scale (mRS) was used. We used the one-month mRS score rather
than the 90-days mRS score as this has been described as outcome in the largest prospective
study describing treatment outcomes in BAO to date 1. Since stroke patients are expected to
continue to recover even beyond this initial period after stroke, this is considered to be a
rather conservative assumption.
We created three health states for patients with BAO ((i) mRS 0-2, (ii) mRS 3-5, and (iii)
BAO related and unrelated death) and two health states for patients without BAO ((i) healthy
and (ii) other death). As the proportion of patients without BAO is the same among all testing
strategies the outcome of patients without BAO does not influence the observed difference
between strategies in this study. Depending on the hazard rate ratio (HRR) of each health state
compared to baseline, patients moved to the dead state. Otherwise they stayed in the health
state.
Data sources and input parameters
Diagnostic test performance.
Data on the performance of NECT were derived from two cross-sectional studies that
compared NECT to CTA as reference standard. Sensitivity of NECT was between 0.61 and
0.71 and specificity was between 0.71 and 0.98 8, 9. Data on the performance of DUS were
derived from cross-sectional studies that compared DUS to CTA. Sensitivity of DUS for BAO
(i.e. obtaining an abnormal instead of a normal result if BAO is present) was between 0.89 3
and 1.0 4, 5. The latter studies applied new contrast-enhanced techniques that might be
responsible for a better diagnostic performance but may be unavailable in an acute emergency
setting. Specificity (i.e. obtaining an abnormal result only if BAO is present) was between 0.5
3
and 0.9 10, 11. Given the still limited available evidence for the diagnostic performance of
DUS, we performed extensive sensitivity analyses around those estimates.
CTA and MRA are considered non-invasive standard tests with a sensitivity and specificity of
close to 1.0 12-14. Un-interpretable images, e.g. due to beam-hardening artifacts (CTA) or
severe patient movement (MRI), were not considered in this model as, other than in DUS,
these are expected to be comparatively rare events for which no precise input data are
available.
Timing to Treatment
Time from symptom onset (TFSO) is a well-known predictor of successful thrombolytic
therapy in the anterior circulation 15. Recently, TFSO has also been shown to influence the
treatment outcome in patients with basilar artery occlusion 16, 17. Consequently, we modeled
TFSO as a factor determining the outcome after initiation of treatment. The distribution of
TFSO was obtained from a study analyzing the BASICS study data 16. We used the data given
in this study to estimate two gamma distributions that represent the distribution of the TFSO
in that study of (i) all patients (Alpha 1.69, Lambda 0.325) and (ii) patients with mild
symptoms (Alpha 2.7, Lambda 0.009). Next, we used these gamma distributions to simulate
the effects of delaying treatment while performing different diagnostic imaging tests. The
study by Vergouwen et al. 16 analyzing the BASICS data was performed for thrombolytic
therapy only. In order to also model the effects of delayed treatment for patients receiving
antithrombotic therapy, we used the distributions of outcome probabilities for patients
receiving thrombolytic therapy in this study 16 in order to estimate outcome probabilities of
patients receiving antithrombotic therapy by further taking into account the average overall
outcome as well as the distribution of time to treatment among patients receiving
antithrombotics 1.
For performing NECT, an additional 10 minutes were added to the initial TFSO. For
performing CTA, an additional 15 minutes were added to the initial TFSO. For performing
MRI, an additional 45 minutes were added to the initial TFSO. For performing DUS, an
additional 30 minutes were added to the initial TFSO.
Adverse Events
We modeled contrast-induced nephropathy due to administration of contrast media during
CTA and risk of fatal radiation-induced cancer due to CT scanning. The risk and consequence
of contrast-induced nephropathy was modeled as previously described 18. In short, contrastinduced nephropathy was estimated to occur in 0.5% of patients receiving contrast medium
during CTA. The additional cost was estimated at $11,409 based on the increased length of
stay in the hospital and dialysis treatment (assuming 5.2 additional days at $1988 per day and
$250 per dialysis treatment) 18.
The radiation risk of cranial CT scanning was modeled with the lifetime attributable risk
using an adapted version of a model previously described for coronary CT angiography 19.
The latency period for radiation-induced cancer was assumed to be ten years. Therefore, the
lifetime-attributable risk was divided by the probability of surviving ten years. We then
converted the lifetime-attributable risk to one-year probabilities by converting the
probabilities to rates, dividing them by the remaining average life expectancy and converting
the one-year rates back to probabilities. In order to reflect mortality, the risk was multiplied
by the fraction of fatal cancers 19. The lifetime attributable risk of cancer for a single cranial
CT scan for ages 35 years and above was obtained from Holmes et al 20 with a risk of 0.0001.
The additional costs were assumed to equal the mean costs of cancer 20. No adjustment for
reduced quality of life was made. The use of NECT and subsequent CTA was assumed to
have an additive effect on the risk of radiation-induced cancer.
We did not model adverse events due to IV thrombolysis in patients without BAO as the only
commonly observed event is orolingual edema 21 with an incidence of about 2%. This,
however, only represents a very short decrease in utility as it can be treated adequately with
anti-histaminergic medication. Additional costs for anti-histaminergic medication are
assumed to be negligible compared to hospitalization and post-hospitalization costs incurred
by stroke patients.
Model Parameter
Expected SE
Value
0.1
0.01-0.2
Distribution
References
Pre-Test Probability
Uniform
Assumption
Outcome probabilities
BAO, thrombolysis 0 to 3 h
1, 16
mRS 0-2
0.49
±20%
Beta
1, 16
mRS 3-5
0.35
±20%
Beta
1, 16
Death
0.16
±20%
Beta
BAO, thrombolysis 4 to 6 h
1, 16
mRS 0-2
0.44
±20%
Beta
1, 16
mRS 3-5
0.35
±20%
Beta
1, 16
Death
0.29
±20%
Beta
BAO, thrombolysis 7 to 9 h
1, 16
mRS 0-2
0.50
±20%
Beta
1, 16
mRS 3-5
0.37
±20%
Beta
1, 16
Death
0.13
±20%
Beta
BAO, thrombolysis > 9 h
1, 16
mRS 0-2
0.22
±20%
Beta
1, 16
mRS 3-5
0.48
±20%
Beta
1, 16
Death
0.30
±20%
Beta
BAO, antithrombotics 0 to 3 h
1
mRS 0-2
0.48
±20%
Beta
1
mRS 3-5
0.44
±20%
Beta
1
Death
0.08
±20%
Beta
BAO, antithrombotics 4 to 6 h
1
mRS 0-2
0.44
±20%
Beta
1
mRS 3-5
0.44
±20%
Beta
1
Death
0.12
±20%
Beta
BAO, antithrombotics 7 to 9 h
1
mRS 0-2
0.48
±20%
Beta
1
mRS 3-5
0.46
±20%
Beta
1
Death
0.06
±20%
Beta
BAO, antithrombotics > 9 h
1
mRS 0-2
0.22
±20%
Beta
1
mRS 3-5
0.61
±20%
Beta
1
Death
0.17
±20%
Beta
Timing data (minutes)
16
Time from symptom onset
310
±189
Gamma
Table I. Input Values with Distribution and Standard Error for Mild Symptoms Analysis.
SUPPLEMENTAL RESULTS
Total costs (US $) QALYs ICER
Overall
CTA
83,324
17.51
DUS + CTA
84,167
17.47
DUS + MRI
84,889
17.44
MRI
84,122
17.49
NECT
85,032
17.44
Mild Symptoms
CTA
37,138
20.25
DUS + CTA
37,199
20.24
DUS + MRI
37,427
20.23
MRI
37,498
20.24
NECT
37,801
20.23
Table II. Costs and Outcomes for Women.
NMB for WTP of
$80,000/QALY
Dominant
Dominated
Dominated
Dominated
Dominated
1,317,755
1,313,290
1,310,221
1,314,936
1,310,180
Dominant
Dominated
Dominated
Dominated
Dominated
1,582,790
1,581,637
1,580,673
1,581,895
1,580,358
A
B
C
D
Figure I. Cost-effectiveness graphs and acceptability curves in female patients. IA and IB
show the results of the overall analysis and IC and ID show the results of the mild symptoms
subgroup analysis. Cost-effectiveness graphs are shown in IA and IC, acceptability curves are
shown in IB and ID. CTA is the optimal strategy in the overall analysis (IA and IB) and for
patients with mild symptoms (IC and ID). CTA = CT angiography, MRI = unenhanced MR
sequences + MR angiography, NECT = Non-enhanced CT, DUS = duplex US.
A
B
C
D
Figure II. Two-way sensitivity analyses exploring a different age of the patients together with
different prior probabilities with a WTP of $80,000 per QALY in the overall analysis (IIA
and B) and patients with mild symptoms (IIC and D). Results for men are given in IIA and C,
for women in IIB and D. Shading = optimal strategy. CTA = CT angiography, MRI = nonenhanced MR sequences + MR angiography, NECT = Non-enhanced CT, DUS = duplex US,
LAR = lifetime-attributable risk.
A
B
C
D
Figure III. Three-way sensitivity analyses exploring different sensitivities and specificities of
DUS and different prior probabilities with a WTP of $80,000 per QALY in women. IIIA and
IIIB show the results of the overall analysis. IIIC and IID show the results of the mild
symptoms subgroup analysis. Shading = optimal strategy. CTA = CT angiography, MRI =
non-enhanced MR sequences + MR angiography, NECT = Non-enhanced CT, DUS = duplex
US.
A
B
C
D
Figure IV. Two-way sensitivity analysis exploring different lifetime-attributable risks of
radiation-induced cancer together with different prior probabilities in the overall analysis
(IVA and B) and patients with mild symptoms (IVC and D). Results for men are given in
IVA and C, for women in IVB and D. Shading = optimal strategy. CTA = CT angiography,
MRI = non-enhanced MR sequences + MR angiography, NECT = Non-enhanced CT, DUS =
duplex US, LAR = lifetime-attributable risk.
A
B
C
D
Figure V. Two-way sensitivity analysis on the time to perform DUS and the prior probability
in the overall analysis (VA and B) and patients with mild symptoms (VC and D). Results for
men are given in VA and C, for women in VB and D. Shading = optimal strategy. CTA = CT
angiography, MRI = non-enhanced MR sequences + MR angiography, NECT = non-enhanced
CT, DUS = duplex US.
SUPPLEMENTAL REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Schonewille WJ, Wijman CA, Michel P, Rueckert CM, Weimar C, Mattle HP, et al.
Treatment and outcomes of acute basilar artery occlusion in the basilar artery
international cooperation study (basics): A prospective registry study. Lancet Neurol.
2009;8:724-730
Mattle HP, Arnold M, Lindsberg PJ, Schonewille WJ, Schroth G. Basilar artery
occlusion. Lancet Neurol. 2011;10:1002-1014
Brandt T, Knauth M, Wildermuth S, Winter R, von Kummer R, Sartor K, et al. Ct
angiography and doppler sonography for emergency assessment in acute basilar artery
ischemia. Stroke. 1999;30:606-612
Kermer P, Wellmer A, Crome O, Mohr A, Knauth M, Bahr M. Transcranial colorcoded duplex sonography in suspected acute basilar artery occlusion. Ultrasound Med.
Biol. 2006;32:315-320
Koga M, Kimura K, Minematsu K, Yamaguchi T. Relationship between findings of
conventional and contrast-enhanced transcranial color-coded real-time sonography
and angiography in patients with basilar artery occlusion. AJNR Am. J. Neuroradiol.
2002;23:568-571
Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al.
Endovascular therapy after intravenous t-pa versus t-pa alone for stroke. N. Engl. J.
Med. 2013;368:893-903
Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: A systematic analysis
comparing intra-arterial and intravenous thrombolysis. Stroke. 2006;37:922-928
Connell L, Koerte IK, Laubender RP, Morhard D, Linn J, Becker HC, et al.
Hyperdense basilar artery sign-a reliable sign of basilar artery occlusion.
Neuroradiology. 2012;54:321-327
Goldmakher GV, Camargo EC, Furie KL, Singhal AB, Roccatagliata L, Halpern EF,
et al. Hyperdense basilar artery sign on unenhanced ct predicts thrombus and outcome
in acute posterior circulation stroke. Stroke. 2009;40:134-139
Hoksbergen AW, Legemate DA, Ubbink DT, Jacobs MJ. Success rate of transcranial
color-coded duplex ultrasonography in visualizing the basal cerebral arteries in
vascular patients over 60 years of age. Stroke. 1999;30:1450-1455
Stolz E, Nuckel M, Mendes I, Gerriets T, Kaps M. Vertebrobasilar transcranial colorcoded duplex ultrasonography: Improvement with echo enhancement. AJNR Am. J.
Neuroradiol. 2002;23:1051-1054
Ng KW, Venketasubramanian N, Yeo LL, Ahmad A, Loh PK, Seet RC, et al.
Usefulness of ct angiography for therapeutic decision making in thrombolyzing
intubated patients with suspected basilar artery thrombosis. J. Neuroimaging.
2012;22:351-354
Bonatti G, Ferro F, Haglmuller T, Pernter P, Naibo L. Basilar artery thrombosis:
Imaging and endovascular therapy. Radiol Med. 2010;115:1219-1233
Wentz KU, Rother J, Schwartz A, Mattle HP, Suchalla R, Edelman RR. Intracranial
vertebrobasilar system: Mr angiography. Radiology. 1994;190:105-110
Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to
treatment with intravenous alteplase and outcome in stroke: An updated pooled
analysis of ecass, atlantis, ninds, and epithet trials. Lancet. 2010;375:1695-1703
Vergouwen MD, Algra A, Pfefferkorn T, Weimar C, Rueckert CM, Thijs V, et al.
Time is brain(stem) in basilar artery occlusion. Stroke. 2012;43:3003-3006
Greving JP, Schonewille WJ, Wijman CA, Michel P, Kappelle LJ, Algra A. Predicting
outcome after acute basilar artery occlusion based on admission characteristics.
Neurology. 2012;78:1058-1063
18.
19.
20.
21.
Jackson D, Earnshaw SR, Farkouh R, Schwamm L. Cost-effectiveness of ct perfusion
for selecting patients for intravenous thrombolysis: A us hospital perspective. AJNR
Am. J. Neuroradiol. 2010;31:1669-1674
Genders TS, Meijboom WB, Meijs MF, Schuijf JD, Mollet NR, Weustink AC, et al.
Ct coronary angiography in patients suspected of having coronary artery disease:
Decision making from various perspectives in the face of uncertainty. Radiology.
2009;253:734-744
Holmes MW, Goodacre S, Stevenson MD, Pandor A, Pickering A. The costeffectiveness of diagnostic management strategies for adults with minor head injury.
Injury. 2012;43:1423-1431
Ottomeyer C, Sick C, Hennerici MG, Szabo K. [orolingual angioedema under
systemic thrombolysis with rt-pa: An underestimated side effect]. Nervenarzt.
2009;80:459-463