New and old strategies to afford the liberal use of drug-eluting stents in real-life scenarios
1University of Ferrara, Italy
2Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS Gussago (BS), Italy
3Erasmus Medical Center, Thoraxcenter, Rotterdam, The Netherlands
4Health Economics, Johnson & Johnson, Cordis Corporation, Italy
* Corresponding author. Tel: +39 0532 202143; fax: +39 0532 241885. E-mail address: vlgmrc{at}unife.it
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Abstract |
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Drug-eluting stents represent one of the most important improvements in interventional cardiology by decreasing the rate of restenosis dramatically. However, at present, cost constraints and a lack of incremental reimbursement have limited their utilization in daily practice in many countries, including Europe. Strategies to implement the liberal use of sirolimus-eluting stents (SES), especially in the primary percutaneous coronary intervention setting where the cost-effectiveness profile could be less favourable, without affecting medical expenditure are presented and discussed. To project the potential cost-effectiveness of SES-supported multivessel treatment compared with that of coronary artery bypass grafting, a decision- analytical model was developed from a payer's perspective on the basis of data derived from the current Italian health-care system.
Key Words: Drug eluting stent • Glycoprotein IIb/IIIa inhibitors • Cost-effective
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Introduction |
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Coronary artery disease is the number one cause of death in Europe and USA for both men and women. Over the past few decades, several new therapies have been developed to treat this disease, and to improve patient care and prevent adverse events. Among them, the growing use of coronary stents is one of the most striking clinical developments in the field of interventional cardiology. Beginning with the first uncontrolled reports of the value of coronary stenting after balloon angioplasty 10–14 years ago,1,2 this treatment has become an integral part of most percutaneous coronary interventions (PCI) that have been driven by the results of several major randomized3–5 controlled clinical trials. However, the long-term success of coronary stents is limited by in-stent restenosis, which occurs in 30–50% of patients within 6 months of balloon angioplasty. Restenosis has been reduced to 20–30% by the implantation of stents, but it still remains a significant challenge. The systematic or local delivery of several pharmaceuticals has been generally unsuccessful in preventing restenosis after coronary interventions.6 Thus, the development of drug-eluting stents (DES) has been needed to counteract high in-stent restenosis rates seen in many patient subgroups after bare-metal stenting (BMS). The results of the first generation of DES have demonstrated a significant reduction in angiographic and clinical restenosis rates,7–9 leading to the adoption of two currently approved DES in medical practice: the sirolimus-eluting coronary stent (SES; Cypher®, Cordis, Warren, NJ, USA), and the paclitaxel-eluting coronary stent (PES; Taxus®, Boston Scientific, Natick, MA, USA). Based on the impact these DES have already had on clinical practice, this technology has transformed the field of interventional cardiology, appearing to have as much impact as angioplasty and BMS when these procedures were introduced. However, important concerns about the costs of DES have been raised,10 and use of DES among different countries is at least partially affected by the presence of specific reimbursement for DES. Consequently, there is a real need to determine the economic value of these devices in the current health-care system, as well as the trade-off between their additional cost and improvements in clinical outcome (i.e. the cost-effectiveness of these devices).
This article presents a two-step approach, aimed at unravelling the economical value of DES in the current health-care system. The first step, which comes from the fusion of clinical and economical skills, encompasses the possibility of adopting specific strategies aimed at absorbing the additional cost of DES compared with BMS, such as choosing to offer less expensive—but not necessarily less effective—treatment/pharmacological combinations in patients selected to receive DES as part of the revascularization strategy. This possibility should be particularly encouraged in patient/lesion subgroups where DES will be less likely to be cost-effective or where the recommended adjunctive pharmacological treatment is particularly expensive, such as during acute myocardial infarction (MI). This intermediate approach has the advantage of neutralizing the incremental cost of DES compared with BMS at baseline, thus encouraging the liberal use of DES from a hospital's perspective.
The second step is based on a decision-analytic model developed from a third-party payer's perspective that evaluates both the long-term effect of DES on resource utilization and the need for re-intervention, and integrates this information with the expected economical consequences of shifting patients from coronary artery bypass grafting (CABG) to PCI accomplished through the use of DES.
The first step: how can the short-term incremental cost of DES be offset in the widely diffused budget restriction era?
Despite the fact that manufacturers have progressively discounted prices for DES, since their introduction into the European and American markets, DES continue to be approximately three to four times as costly as BMS. In Italy, for example, the average acquisition cost for a single DES is in the range of 1600–1800
, which is around three times higher than the average acquisition cost for a BMS.
From a hospital's perspective, the liberal use of DES would therefore exert a tremendous impact on the final budget, and mechanisms that can overcome this consequence are in demand until specific reimbursements for DES are provided. As a paradigm of the second step, we will discuss (see subsequent section) one possible approach recently investigated by our group to overcome the cost of DES in the specific setting of acute MI, in which current clinical guidelines specifically recommend abciximab.11
Interestingly, abciximab and DES implantation have potentially complementary effects on death/acute MI and the need for re-intervention in the setting of AMI,12–16 providing a rationale for testing their combination in this setting.17 However, both these therapies are expensive and any potential clinical benefit from combination therapy would be counterbalanced by a considerable increase in overall medical expenditure. The average cost of combining abciximab treatment with a single SES exceeds 50% of current reimbursement for acute MI in some European countries.18 Thus, financial pressure may lead to competitive use between DES and abciximab on the basis of their high cost.19
In a previously reported head-to-head comparison between abciximab and tirofiban in patients undergoing PCI, abciximab was superior to tirofiban with respect to the pre-specified combined endpoint.20 The superiority of abciximab was driven by a higher rate of peri-procedural acute MI in the tirofiban arm, suggesting inadequate early platelet inhibition with the bolus regimen (10 µg/kg) employed. Subsequent dose-ranging studies showed that increasing the tirofiban bolus dose from 10 to 25 µg/kg was necessary to obtain an optimal level of platelet inhibition,21 and results from initial clinical trials with this higher bolus dose appear promising.
Replacing abciximab with tirofiban, administered as a single high-dose bolus regimen, is a promising strategy that could preserve financial resources. With current European market prices, this would absorb the additional cost of DES vs. BMS.
Thus, in an attempt to further improve outcome after acute MI without affecting overall costs, we compared angiographic and clinical outcomes after tirofiban-supported infarct artery SES implantation with that following a current preferred strategy for the treatment of ST-elevated MI (STEMI).11,22 Our results demonstrate that a strategy of tirofiban-supported SES implantation during primary PCI was safe and resulted in improved clinical [decreased need for target vessel revascularization (TVR)] and angiographic (decrease in restenosis) outcomes compared with a strategy of abciximab-supported BMS implantation. Moreover, such a strategy was associated with an improved safety profile with regard to thrombocytopenia (Figure 1). In particular, the cumulative incidence of major adverse cardiac events (MACE) (death, MI, or TVR) was significantly lower in the tirofiban–SES group than in the abciximab–BMS group [18% vs. 32%, respectively; hazard ratio (HR), 0.53 (95%CI, 0.28–0.92); P=0.043] (Figure 2).11 Overall, the composite endpoint of death/acute MI was similar in the tirofiban–SES (13%) and the abciximab–BMS groups [17%; HR, 0.71 (95%CI, 0.34–1.5); P=0.4] (Figure 2), but there was a significant reduction in the need for TVR [7% vs. 20%, respectively; HR, 0.30 (95%CI, 0.12–0.77); P=0.01] in the tirofiban–SES group.11
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Interestingly, thrombolysis in MI (TIMI) flow patterns and cumulative ST-segment resolution—both surrogates of long-term mortality, which have been consistently improved by abciximab treatment even in relatively small studies12,13—did not differ between treatment arms (Figure 3),11 a finding supportive of the benefit of tirofiban when used as a single high-dose bolus, compared with the current ‘gold standard’ treatment for STEMI.
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The philosophy behind this study, which is often part of the clinical decision-making, was that the patient is not receiving just a stent or antiplatelet treatment, but their combination, so it makes sense to test the final effect of the combination even more than the separate effect of each treatment alone. However, it should be always kept in mind that new strategies incorporating DES should be prospectively evaluated before they can be recommended. The fact that DES use has not convincingly been associated with any improvement in patient outcome should always be borne in mind if potentially life-saving treatments are negatively selected in favour of these new coronary devices.
The second step: incorporating DES in a formal long-term cost-effectiveness analysis
The increased up-front procedural costs related to DES use have been perceived as an important limitation to more widespread utilization of these devices in Europe. In contrast, a reduction in repeat intervention procedures during follow-up with the use of these devises may save money, which may eventually lower total costs.
Cost-effectiveness of SES-supported treatment of single-vessel disease
In RAVEL (Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions), in which patients with a single discrete coronary lesion were randomly assigned to Bx Velocity stent or a sirolimus-eluting Bx Velocity stent, the group of patients receiving an SES had an estimated additional procedural cost of 1286.23 However, after 1 year, the estimated additional cost difference decreased to 166 because of a reduction in the need for repeat revascularizations in the SES group (0.8% vs. 23.6%; P<0.01).23 Thus, the 1-year data from RAVEL suggest an attractive balance between cost and effect for SES in the treatment of single native de novo coronary lesions.
The cost-effectiveness of DES in more complex lesion subsets was subsequently investigated in the US SIRIUS (Sirolimus-Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions) trial, in which initial hospital costs were increased by US$2881 per patient with the use of SES.24 Over the 1-year follow-up period, use of SES led to substantial reductions in the need for repeat revascularizations, including repeat PCI and CABG compared with the use of BMS. Although, follow-up costs were reduced by US$2571 per patient with SES, aggregate 1-year costs remained US$309 per patient higher than with BMS.24 The incremental cost-effectiveness ratio for SES was US$1650 per repeat revascularization event avoided or US$27 540 per quality-adjusted year of life gained, values that compare reasonably with those of other accepted medical interventions. Thus, despite not being cost-saving in patients undergoing more complex interventions, the use of these devices appears to be reasonably cost-effective within the context of the US healthcare system.
A 1-year cost-effectiveness analysis of the Taxus PES vs. BMS in the TAXUS IV trial (presented by D Cohen at the TCT Meeting, Washington DC, USA, September 2004) revealed an incremental cost-effectiveness ratio for PES of US$4678 per repeat revascularization event avoided or US$47 798 per quality-adjusted year of life gained. Interestingly, in patients with diabetes mellitus and in those presenting with a reference vessel diameter of <2.5 mm, PES implantation was shown to be cost-saving with respect to BMS.
Although, these analyses on DES cost-effectiveness are attractive, it should be emphasized that they refer to randomized controlled studies evaluating DES benefit in single-vessel treatment, and the balance between cost and effect in more complex real-life situations, in which restenosis may occur in a small but sizable number of patients, has to be specifically analysed. Furthermore, the number of stents used per procedure may markedly increase procedural costs, potentially limiting the use of this new technology for the treatment of multivessel disease.
Cost-effectiveness of SES-supported treatment of multivessel disease
As the effect of liberal use of DES in treating multivessel disease compared to CABG is currently unknown, a decision-analytic model was developed from a payer's perspective to project the potential cost-effectiveness of SES compared with patients currently undergoing CABG in the Italian health-care system. The model allows input of health plan-specific data for volume and reimbursement rates for PCI and CABG, and is based on the health-care system of Regione Emilia Romagna (ER) [data retrieved from a national database of the Gruppo Italiano Studio Emodinamica (GISE); available at www.gise.it]. Outcome data and average number of SES per patient were retrieved from the ARTS II database (presented by PW Serruys at the American College of Cardiology Annual Scientific Session, Orlando, FL, USA, March 2005). In 2003, 6957 PCIs with coronary stent implantation were performed in ER, of which 21.8% were classified as multivessel treatment. Specifically focusing on multivessel intervention, where no data on the cost-effectiveness of DES are available from randomized controlled trials, we assumed that: (i) all stents implanted were SES; (ii) device reimbursement to hospitals was 80%, with an acquisition cost of 1800 per SES (costs derived from the current Italian health-care system); (iii) procedural reimbursement for PCI was based on DRG 112 (6715); that for CABG was based on DRG 106 (17 783); and (iv) the average SES per patient was 2.7 in the index procedure and 1.2 in the PCI-based re-treatment (derived from the ARTS II database).
Using these realistic assumptions, treating multivessel disease patients in ER with PCI instead of CABG would result in an overall saving of 10 633 220 over a period of 1-year. Importantly, this comes without consideration of the incremental cost for hospitalization and rehabilitation, which would further improve the cost-saving profile of PCI compared with CABG. Moreover, if there were a further 12% shift from CABG to SES-supported PCI treatment, overall savings would increase to 12 774 063. Thus, multivessel disease treatment with liberal use of SES has the potential to free resources compared with the current costs for CABG. These resources could theoretically be re-allocated in the same health-care system to fund unrestricted use of SES in every stent-supported PCI. Thus, going back to our original model, using the same assumptions but considering an average number of stents per patient of 1.23 (data from the GISE database) and hypothesizing that SES are implanted instead of BMS in all stent-based PCI would result in an overall incremental cost of 12 322 238 at baseline. This would be offset by the savings coming from a 12% shift toward PCI in the treatment of multivessel-disease patients (see previous model on multivessel stenting), with a final overall saving of 451 824, without consideration of the substantial reduction in the need for repeat revascularization, including repeated PCI and CABG in patients receiving single-vessel treatment as shown by the RAVEL and SIRIUS trials. Therefore, the liberal use of DES in our mixed-model based on the current Italian health-care system and data from contemporary SES-supported PCI trials would not only be cost-effective but even cost-saving if only a minor shift from CABG to PCI is anticipated.
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From the hospital's perspective, where liberal use of DES without specific device reimbursement would lead to great increase in medical expenditure, there is potential to implement comprehensive treatment strategies using unrestricted DES without increasing medical costs. This would improve the efficacy of stent-based long-term revascularization in our patient population.
From the third-party payer's perspective, the available literature suggests that single-vessel treatment on the basis of DES implementation is indeed cost-effective even if not cost-saving. Using our decision-analytic model, SES implantation in the treatment of multivessel disease would be cost-saving even if only a minor shift from CABG to PCI is assumed, thus freeing resources to offset the initial incremental cost incurred by using SES in every PCI.
These conclusions, based on a model that incorporates arbitrary cut-offs and a data mixture from both real-life registries and trials should be considered with caution. Confirmation and extension of our preliminary SES-based cost-effectiveness projections to real-life scenarios are clearly required.
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This work was partially supported by a grant from Fondazione Cassa dei Risparmi di Ferrara.
Conflict of interest: M.V. has received honoraria for lectures from Merck & Co. and Guilford. C.G. is a Cordis employee.
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