Article

Cost-effectiveness of Gadofosveset in the Management of Patients with Symptomatic Peripheral Arterial Occlusive Disease

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DOI:https://doi.org/10.15420/ecr.2008.4.1.51

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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Peripheral arterial occlusive disease (PAOD) is a major health risk. The prevalence of PAOD varies with the population observed and the screening method used. In epidemiological studies, measurement of the ankle/brachial index (ABI) is recommended for screening (ABI <0.9 indicates PAOD). Surveys in Germany based on the ABI showed a PAOD prevalence of 2.3% among women aged 45–49 years and of 2.6% among men in the same age group. These rates increase to 10.4 and 15.2% in men and women, respectively, in those aged 70–75 years.1–5 The decreased blood flow to the legs caused by PAOD may be mild to moderate, corresponding clinically to intermittent claudication (IC), or severe, resulting in critical limb ischaemia (CLI).

Both non-invasive and invasive diagnostic procedures are used to confirm the diagnosis of PAOD and to decide on the best method of patient management thereafter. Of the non-invasive methods, Doppler ultrasonography is the most widely used. The current standard of reference is digital subtraction angiography (DSA), but this method is highly invasive, requiring the insertion of an arterial catheter and its manipulation in situ. Magnetic resonance angiography (MRA) on the other hand is minimally invasive, requiring only the venous injection of a contrast agent such as a conventional extracellular contrast medium (ECCM) or blood-pool agents such as gadofosveset trisodium (Vasovist®, Bayer Schering Pharma AG), referred to hereafter as gadofosveset. Gadofosveset is at present the only approved blood-pool contrast agent, having received marketing authorisation in the EU in 2005 and in Australia, Canada and Switzerland in 2006.

Research on the cost and outcomes of diagnostic imaging procedures started with the first controlled randomised studies in lung and breast cancer in the 1960s and 1970s. New diagnostic procedures such as non-invasive MR or computed tomography (CT) angiography were shown to not only reduce costs but also provide benefits for patient management.6 Recent studies have reported that newly developed medical products lead to higher costs for the healthcare system when they do not replace but rather are used in addition to existing products or when they cost more than those replaced.7 In contrast to other areas of medicine, cost and outcomes research in diagnostics is fundamentally different because of the time distance between cause and effect, i.e. between diagnosis and patient management. The radiologist’s primary task is to provide an accurate diagnosis using the appropriate diagnostic procedure. However, patient management might be altered by a change in working diagnosis that is beyond the control of the radiologist.

The cost and utility of a new diagnostic method are often analysed based on its technical diagnostic value, i.e. sensitivity and specificity. However, these do not necessarily fully reflect all of the incremental benefits of a new diagnostic imaging modality on diagnostic and therapeutic decision-making.8,9 Parameters such as diagnostic confidence are clinically important to aid the physician in establishing an accurate diagnosis by avoiding additional procedures to confirm the diagnosis.

In the following study, diagnostic confidence was used for the cost-effectiveness evaluation of gadofosveset-enhanced MRA in CLI and IC. Diagnostic confidence is based on the physician’s subjective certainty when providing a diagnosis. In cases of no or low confidence, another diagnostic procedure would be required. A decision-tree model was used to compare the cost–utility ratios of different imaging strategies in the diagnosis and treatment of CLI and IC.

Materials and Methods
Data Sources
Procedure Characteristics, Treatment and Follow-up

Data on the diagnostic confidence of gadofosveset-enhanced MRA in CLI and IC from clinical studies were not available at the time of the modelling. A Delphi panel10 approach was therefore used to generate such data. The Delphi panel in this study consisted of the following clinical experts: five interventional radiologists and one vascular surgeon with expertise in diagnosis and intervention. All had extensive practical clinical experience with gadofosveset. The probabilities for the risks of percutaneous transluminal angioplasty (PTA), bypass and amputation following each of the initial imaging modalities were also obtained from the Delphi panel. These were used to populate the model. The probability of renal failure was derived from the literature.

Health-related Quality of Life

Quality-adjusted life-years (QALYs) were calculated as the sum of health values for each health state multiplied by the amount of time spent in those states. Health-related QALYs were expressed as values ranging from 0 (death) to 1 (full health).

Utility Values

Utilities were assigned to each state or combination of states. In general, the utilities used were derived from an analysis conducted by Holler.11 As combined events, such as amputation followed by dialysis, were not part of Holler’s examination, the utility for each combined event was discounted by 0.12 on the basis of considerations by Redekop et al.12 This analysis used an EQ-5D utility score and demonstrated a difference of 0.12 in scores between macrovascular complications only and a combination of micro- and macrovascular complications. The utility values used for the different events are shown in Table 1. These values were then weighted with the respective years of life expectancy after each event within the model. The annual utility values were discounted by 5%13 and aggregated over the respective lifetimes (see Table 1). The utility values for events in IC were derived in the same manner as those in CLI; however, amputation was not considered in IC, as this outcome is extremely unlikely.

Costs

Treatment costs were evaluated from the perspective of the payer and the hospital. The ‘payer perspective’ reflects the relevant costs for the system of statutory health insurance operating in Germany (gesetzliche Krankenkassen); the ‘hospital perspective’ reflects the relevant costs incurred by hospitals, i.e. the costs per procedure and costs for hospitalisation. For the hospital perspective it was further assumed that all diagnostic procedures and further therapies occur within the hospital sector as event costs; thus, the possibility of repeat hospitalisations after the primary one was not taken into account. Bypass and amputation were assumed to be conducted as inpatient procedures, while for CLI 20% of MRA, DSA (standard and selective) and PTA procedures were assumed to be conducted as outpatient procedures. For IC, MRA was considered as an outpatient procedure in 100% of cases, and DSA and PTA in 50% of cases.

Cost data were obtained by reference to appropriate tariffs and doctors’ fee scales from the perspective of statutory health insurance. Legally required discounts (e.g. to pharmacies) and the required contribution by patients were taken into account. All cost data collected were single-event costs, except for costs of dialysis (here regarded as a lifelong requirement) and amputation with CLI (requiring event costs plus costs of long-term support measures).

Outpatient cost data were taken from the German unified doctors’ fee scale EBM 2000 plus.14 Costs for the stay in hospital were derived from the German Diagnosis-related Groups (DRGs) Version 2006.15 Since inpatient services are generally remunerated as a lump sum by the German DRGs, costs were estimated based on the tariff scheme of the German Hospital Federation (DKG-NT16), which is often used for internal accounting. Drug costs and prices of contrast media were obtained from a current price list (ifap®-Index17). The lifetime costs for dialysis and amputation were calculated on the basis of literature figures13 and discounted by 5% per annum.

Lifetime costs for dialysis and amputation due to CLI were calculated on the assumption of a remaining life expectancy according to either published data or the Declining Exponential Approximation of Life Expectancy (DEALE) method.18 The costs per procedure and costs for hospitalisation were considered. In accordance with EBM 2000 plus, the consultation complex for the radiologist (outpatient) was counted only once, assuming that all patient contacts with the radiologists took place in the same quarter-year. Owing to the similarities between CLI and IC in terms of treatment pathway and model structure, most costs were used for both groups; only the costs for dialysis were adjusted for the longer life expectancy in IC.

Decision Model

A decision model was used for the cost-effectiveness analysis including costs for the pre-treatment diagnostic work-up and subsequent patient management. QALYs were used to determine the cost-effectiveness of gadofosveset-enhanced MRA versus ECCM-enhanced MRA. Within the diagnostic work-up, the physician could choose one of three initial alternatives – gadofosveset-enhanced MRA, ECCM-enhanced MRA or standard intra-arterial (IA)-DSA – to confirm stenosis of a vessel and the location of the target obstruction as previously diagnosed by ultrasound (see Figure 1). In case the physician was not confident enough to decide on further treatment based on the intial method, it was assumed that a further diagnostic modality was required. Variables for costs, probabilities and utility parameters were defined in the model and assigned to the respective health states. To obtain data for the tree, a literature search was conducted to collect data on resource use, probabilities and utilities.11,12,18,23–30

The following patient management options were considered after diagnosis: selective IA-DSA followed by PTA when needed, bypass surgery or no intervention. In patients with CLI, amputation was also considered. Patients who undergo PTA or DSA may incur renal failure because of the contrast medium. If renal failure occurs, the patient may thereafter have to undergo lifelong dialysis. In the absence of diagnostic confidence a confirmatory selective DSA – or gadofosveset-enhanced MRA in base case II – was conducted. The same therapeutic options as listed above were then provided (PTA, bypass surgery, amputation or no intervention). Initial ECCM-enhanced MRA leads to slightly different diagnostic options. If diagnostic confidence was not attained, gadofosveset-enhanced MRA was considered as an alternative to confirmatory selective DSA. The PAOD decision tree was developed using Data Treeage® software (Williamstown, MA, US).

Cost-effectiveness Analyses

The model was intended to generate cost–utility information on the initial use of gadofosveset-enhanced MRA as opposed to ECCM-enhanced MRA or standard DSA in patients with either IC or CLI. Resulting therapeutic options were: PTA in the same session (in connection with selective DSA), PTA in a second session, bypass and (as a last resort) amputation. The principal outcomes in the model were QALYs and lifetime costs. A strategy was considered dominant if it yielded more QALYs at lower costs.

Base-case Analysis

Base case I was defined according to the current liability law in Germany, which requires a confirmatory DSA in all cases where amputation is considered. A second scenario, base case II, was developed for situations where this legal obligation ceases to apply; here, instead of a confirmative selective DSA, additional diagnostic MRA with gadofosveset or conventional ECCM was considered. Both base cases were investigated in parallel in order to find out the effect of this legal requirement.

Sensitivity Analyses

To test the robustness of the model, sensitivity analyses were conducted in which several pivotal parameters of the model were varied (procedure costs, lifetime dialysis costs, probability of dialysis, diagnostic confidence, frequency of inpatient versus outpatient treatment and utility values). Only the most influential and clinically relevant results of the sensitivity analyses are reported in the results.

Results
Critical Limb Ischaemia
Base-case Analysis

The results for the payer and hospital perspectives are displayed in Table 2. From the perspective of both the payer and the hospital, the management of PAOD with initial use of gadofosveset-enhanced MRA was found to be less costly than initial use of ECCM-enhanced MRA or standard DSA, while showing equivalent utility. Results for base cases I (selective DSA to be performed as confirmative imaging modality before amputation) and II (gadofosveset-enhanced MRA as an alternative confirmative imaging modality before amputation) were almost identical.

Sensitivity Analyses

Several pivotal parameters of the model were varied (procedure costs, lifetime dialysis costs, probability of dialysis, diagnostic confidence, frequency of inpatient versus outpatient treatment and utility values). In general, these variations did not lead to changes in the ranking of the diagnostic alternatives. However, the result of the model-based calculation is necessarily sensitive to variations in some of the parameters. The results of some two-way sensitivity analyses are presented in Figure 2; the probabilities of bypass with gadofosveset-enhanced MRA and ECCM-enhanced MRA were varied to determine the sensitivity of the outcome to these two modalities. Initial gadofosveset-enhanced MRA was found to be less costly when the probabilities of a bypass following ECCM-enhanced MRA and gadofosveset-enhanced MRA are in the range as defined by the Delphi panel (see Table 1). In all scenarios evaluated, initial standard DSA was found to be more costly than the comparative procedures, as shown in Figure 2.

Figure 3 displays the comparison of the parameter of ‘threat of amputation’ following MRA with gadofosveset and with ECCM. Again, the cost advantages of gadofosveset-enhanced MRA were stable within a range of probabilities. Initial standard DSA was found to be more costly in each scenario.

Outpatient cost data were taken from the German unified doctors’ fee scale EBM 2000 plus.14 An EBM-point value of €0.0511 was used (this is the maximum value; however, it varies throughout the country and may be as low as ~40% of this in some regions of eastern Germany). A sensitivity analysis (results not shown) demonstrated that (downward) deviations from €0.0511 had only a small influence on the conclusions of this work and tended, if anything, to reinforce them; therefore, only the results for €0.0511 are shown.

In addition, the impact of diagnostic confidence was analysed. From the payer perspective, initial gadofosveset-enhanced MRA was always found to be the least costly option compared with ECCM-enhanced MRA and standard DSA. From the hospital perspective, this superiority of gadofosveset-enhanced MRA was found to change when the probability of obtaining diagnostic confidence from initial gadofosveset-enhanced MRA was lower than about 0.58 for base case I and lower than about 0.55 for base case II.

Finally, an analysis of the number of amputations expected on the basis of the various decision-tree branches was performed. For base case I, the average number of amputations per case expected was 0.087 after initial standard DSA and 0.085 after initial ECCM- or gadofosveset-enhanced MRA. For base case II the number of amputations expected was 0.085 irrespective of the initial diagnostic method.

Intermittent Claudication
Base-case Analysis

For both the payer and the hospital perspective (except base case II from the hospital perspective), the management of PAOD initially using gadofosveset-enhanced MRA is less costly, while showing equivalent utility to ECCM-enhanced MRA or standard DSA. For base case II, gadofosveset-enhanced MRA and ECCM-enhanced MRA are used more often if diagnostic confidence is not obtained from the first modality. The results of the economic model from both the payer and hospital perspectives are displayed in Table 3.

Sensitivity Analysis

With regard to sensitivity analyses, the results of the models generally stayed robust. However, from a hospital perspective the results for IC are more sensitive compared with the results for our other scenarios. For example, as shown in Figure 4, the advantage of gadofosveset compared with ECCM changes when the probability of bypass following gadofosveset-enhanced MRA is lower than about 0.07 and that following ECCM-enhanced MRA is higher than 0.10.

The sensitivity analyses on the correlation between the probabilities of PTA with gadofosveset and with ECCM are shown in Figure 5. Here, the advantage changes in favour of conventional ECCM when the probability of PTA following gadofosveset-enhanced MRA is lower than 0.57 and the corresponding probability following ECCM-enhanced MRA is higher than 0.60.

The effect of diagnostic confidence was also analysed for IC from the payer and hospital perspectives. With regard to base case I, from the payer perspective no advantage of gadofosveset-enhanced MRA over ECCM-enhanced MRA was found when the diagnostic confidence of ECCM-enhanced MRA was set higher than 0.85 (see Figure 6). Considering the comparison between the diagnostic confidence following gadofosveset-enhanced MRA and standard DSA from a payer perspective (base case I), no advantage of gadofosveset-enhanced MRA over DSA was found when the diagnostic confidence of the MRA is below 0.85. For base case II, ECCM-enhanced MRA was found to be a more advantageous option compared with gadofosveset when the diagnostic confidence with ECCM-enhanced MRA is above 0.83 and that with gadofosveset-enhanced MRA is lower than 0.94. The sensitivity analyses for diagnostic confidence of gadofosveset-enhanced MRA compared with ECCM-enhanced MRA and standard DSA from a hospital perspective show that the results of the model are robust for a diagnostic confidence of more than 0.68 with gadofosveset-enhanced MRA in base case I. For base case II, the results of the model were sensitive to variations in diagnostic confidence. Here, gadofosveset-enhanced MRA was mostly dominated by conventional ECCM-enhanced MRA.

Discussion

In 2008, Ouwendijk et al.32 published an economic evaluation of the cost and effects of MRA in the diagnostic work-up of the lower extremities. They compared Doppler ultrasonography, MRA and CT angiography (CTA), and concluded that MRA and CTA are superior to Doppler ultrasonography with significantly higher confidence and less additional imaging. Costs were lowest with CTA,32 but Ouwendijk et al. did not take into account gadofosveset-enhanced MRA. In our economic modelling, the cost-effectiveness of gadofosveset-enhanced MRA was investigated compared with ECCM-enhanced MRA and DSA.

We did not take into account the less frequently used imaging option CTA as it is not the preferred option in patients with CLI due to the often heavily calcified peripheral arterial system. A decision tree was used to model the diagnostic confidence (confident/ not confident) with regard to costs for the subsequent management of the patient. Data from several sources (e.g. published data and data obtained from experienced clinicians such as the Delphi panel) were obtained to conduct the analysis. Several randomised clinical studies are ongoing to observe the diagnostic confidence of the three imaging procedures – DSA and gadofosveset- and ECCM-enhanced MRA – within the same trial setting. As these data are not yet available, data from the Delphi panel were used for this initial modelling. As soon as these data become available, however, the model should be revised to reflect these results.

According to the initial cost–utility calculations described in this article, a diagnostic strategy using gadofosveset-enhanced MRA as the initial diagnostic modality has been shown to be a cost-effective option for the work-up of PAOD compared with ECCM-enhanced MRA or with standard DSA, from both the payer and the hospital perspective, for CLI and IC.

Sensitivity analyses were performed by varying crucial parameters in the model, and the robustness of the results of the model-based calculations were demonstrated. Examples are life expectancy and rates of in- and outpatient procedures; other parameters include comparative data on diagnostic confidence translating into therapeutic decision-making and comparative data on costs and utilities in PAOD.

Whenever possible, utilities were derived from the literature, taking into account the respective health status (CLI with amputation and dialysis, CLI with PTA, IC with no interventions, etc.). Missing probability data – especially concerning diagnostic confidence and transitions to different treatment options and health states, as well as percentages of inpatient versus outpatient procedures in the two different patient subgroups – were obtained by a Delphi panel survey.10 Note that in general, according to the estimates of the Delphi panel experts, selective DSA was regarded as being equivalent to gadofosveset-enhanced MRA, with both being considered superior to ECCM-enhanced MRA and standard DSA. Discounting of costs and utilities was performed where appropriate. The effects of the critical parameters on the result of the model-based calculation were evaluated in the sensitivity analysis.

Only minor differences were found between the three diagnostic strategies with respect to their therapeutic implications and, subsequently, to QALYs. Initial use of gadofosveset-enhanced MRA leads to a reduced utilisation of diagnostic procedures compared with ECCM-enhanced MRA and standard DSA. This is due to a higher diagnostic confidence, as assumed for gadofosveset-enhanced MRA. This reduction in resource use translates into reduced costs. QALYs remain unchanged as reduced resource use in diagnosis does not necessarily lead to a reduction in the frequency and expense of patient management (e.g. dialysis, amputation, PTA or bypass).

One of the most invasive patient management strategies in the current model was amputation. The Delphi panel expected gadofosveset-enhanced MRA and selective DSA to be superior to ECCM-enhanced MRA and standard DSA in this respect, with amputation rates of 8.5 and 12.5%, respectively. This is based on their ability to detect patent outflow vessels suitable for bypass surgery instead of amputation. The final diagnosis in the model does not reflect this difference as additional confirmatory diagnosis by gadofosveset-enhanced MRA or selective DSA was required after proposing amputation with ECCM-enhanced MRA. The potential benefit of gadofosveset-enhanced MRA in terms of avoiding unnecessary amputations needs further investigation by a clinical trial and/or other research.

For the cost calculations only one DSA series per case was included in the calculation. However, in practice several examinations are often necessary and are charged to the funding agency, which in turn further increases the costs of DSA.

The accuracy of ECCM-enhanced MRA is well known from the literature, whereas the first data on the accuracy of gadofosveset-enhanced MRA (97%) were presented by Bonel et al. in 2007 from a small study using DSA as standard of reference.32 Another study, presented by Vogt et al. in 2008, showed that the accuracy of gadofosveset-enhanced MRA (85%) is not inferior to that of ECCM-enhanced MRA (86%), but the number of non-assessable images was found to be lower with gadofosveset (5–18 versus 9–28%).33 More clinical studies are ongoing to provide not only the diagnostic value in terms of sensitivity, specificity and accuracy, but also data on diagnostic confidence, assessed in intra-individual comparison trials with all three procedures – DSA and gadofosveset- and ECCM-enhanced MRA.

Overall, this cost-effectiveness analysis showed promising results, especially in view of the use of ‘real-world’ diagnostic confidence as obtained from the Delphi panel in constructing the model and predicting its consequences. Nevertheless, further research with regard to efficacy, utility and resource use for diagnostic procedures in PAOD will be required, along with additional sensitivity analyses to further evaluate the effects of several parameters based on the findings of the ongoing clinical studies with respect to the diagnostic confidence. Ôûá

Acknowledgements

The Delphi panel comprised the following experts: Dr A Huppertz (Charité, Berlin), Dr T Leiner (Maastricht University Hospital, The Netherlands), Dr K Nikolaou (University Hospital Großhadern, Munich), Dr R Puls (University Hospital, Greifswald), Dr J Rieger (University Hospital Innenstadt, Munich), Dr T Überrück (University Hospital, Jena) and Dr W Willinek (Radiological University Hospital, Bonn). We thank them warmly for their contribution to this work.

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