Recently, many eminent scientific journals have published long-term follow-up data from both randomised clinical trials (RCTs) and registries of patients treated with percutaneous coronary intervention (PCI) undergoing drug-eluting stent (DES) implantation. In fact, this is the only course of action to address the concerns regarding DES safety that were first raised almost two years ago.1 Currently, even in the presence of reassuring data,2 the matter of risk–benefit and cost-effectiveness of these devices provokes heated debate within the scientific community.
A recently published study3 is fuelling the ongoing discussion. With the use of a decision analytic model, the authors ambitiously sought to define at what point the incremental risk of very late stent thrombosis in DES would outweigh the restenosis benefit compared with a bare metal stent (BMS). They concluded that even a small absolute increase in DES thrombosis compared with BMS after one year (0.14%/year) would result in BMS being the preferred strategy for the overall PCI population. Notably, they observed that when the baseline risk of restenosis increased – as observed in diabetic patients, small vessels and/or long lesions – the annual probability of very late stent thrombosis above which DES would no longer be the preferred revascularisation strategy also increased.
Perhaps unsurprisingly, the patients who benefit most from DES in terms of net clinical outcome are those for whom DES does not represent an on-label indication. These findings are consistent with recent reports of DES use in off-label settings4–10 and are interesting from a professional perspective following a re-reading of our findings from the recently published multicentre prospective Sicilian DES Registry,11 whose experimental design and eligibility criteria specifically included the presence of one or more angiographic characteristics associated with an increased risk of restenosis after BMS use.
Although the benefits of widespread DES use in clinical practice may appear obvious in light of the latest findings, when the study was planned it represented a potential hazard as follow-up data were lacking on potential outcomes of high-risk patients habitually excluded from pivotal RCTs.
The study was conducted by the Sicilian Health Service Authority, which sustained 50% of the cost of devices in addition to Diagnosis-Related Group (DRG) reimbursement. The nine participating Sicilian hospitals – all with a lot of experience in interventional cardiology and a high volume of procedures per year – supported the remaining 50% of purchases. This allowed the use of the most modern and potentially effective available stent to be extended to the largest number of patients possible, in a region that traditionally lags behind more recent developments in both the scientific and technological fields.
Briefly, the Sicilian DES registry collected data on 1,472 consecutive patients (mean age 61.9±10 years, 80.7% men) with suspected coronary artery disease who underwent coronary angiography between June 2004 and February 2005 and stent implantation with either sirolimus-eluting stents (SES) (781 patients, 1,222 lesions) or paclitaxel-eluting stents (PES) (691 patients, 1,217 lesions) in the presence of at least one of the following indications: ostial lesion of one or more major coronary artery (9.4%), multivessel disease (defined as the involvement and treatment of at least two major epicardial vessels or the major epicardial vessel and a branch ≥2.5mm in diameter originating from another major epicardial vessel) (51%), lesion length ≥20mm (50.8%), total occlusions (2.6%), lesions at the bifurcation level (11.2%), diffuse in-stent restenosis (6.5%) and lesion in a saphenous graft or an internal mammary bypass (2.2%). Of the treated lesions, 11% had a final minimal lumen diameter <2.5mm, 74% were American College of Cardiology/American Heart Association (ACC/AHA) B2/C type and off-label indications accounted for 49.3%. Finally, 32.1% of patients were diabetics and 61% were treated in the setting of an acute coronary syndrome (ST-segment elevation myocardial infarction in 14.8%).
Overall, these features identified a challenging population that was comparable to those in other registries collecting nine- to 12-month follow-up.9,12–18 However, 42.6% of the patients in the Sicilian DES registry had multivessel stenting, whereas in the other reports evaluated this procedure was performed in 8.6–32% of patients. Clinical and angiographic follow-up at 9±1 months were 98 and 83%, respectively. All-cause mortality at 1.7% was below the range of 2.2–5.3% that was previously reported, whereas the incidences of myocardial infarction (2.7%) and target vessel revascularisation (TVR) (6.5%) were consistent with other registries.9,12–18
The finding of lower TVR rates in randomised trials19–21 is probably associated with the high-risk characteristics of patients enrolled in this registry, e.g. 16% of diabetics in the Randomized Study with the Sirolimus-Coated Bx Velocity Balloon- Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) trial.19
According to the Academic Research Consortium (ARC) classification,22 definite stent thrombosis was observed in 11 cases (0.7%; two acute, five subacute, four late stent thrombosis), probable stent thrombosis in 22 cases (1.5%; six acute, 14 subacute, two late stent thrombosis) and possible stent thrombosis in three cases (0.2%; all late by definition). Thus, the overall incidence was 2.4% with a fatal event rate of 44%.
Although these data are satisfactory, it is of note that the need for any kind of revascularisation was 12.1%, and 4.7% of patients needed repeat intervention for disease progression in a target or non-target vessel. This finding emphasises the observation that even PCI with DES can be less effective than coronary artery bypass grafts (CABGs) in achieving complete and lasting revascularisation, with the latter being associated with a better long-term outcome in various studies. Moreover, similar to all innovative technologies, DES has an economic impact coinciding with the clinical one. Although several available studies showed that DES is more effective than BMS in reducing restenosis,19–21 it must be considered that the rationality of public coverage of a health service should be driven not only by efficacy criteria but also by economic reasons. In fact, the market price has almost unanimously been perceived as the major limitation for more widespread worldwide use of DES.23 Therefore, especially in situations where resources are scarce, it appears necessary to consider the improvement of public health as the effect of good choices on the subject of cost-effectiveness.
Concerning the cost-effectiveness of DES versus BMS, some analyses that reached different conclusions have been published.24–27 The study of Shrive et al.25 obtained efficacy data from a meta-analysis of four RCTs, and estimated a value of almost CA$58,000 for every earned quality-of-life- adjusted life-year (QALY). This value became more favourable when the subgroups of diabetics and patients >75 years of age were considered.
The US study of Cohen at al.,26 which used efficacy data from the Sirolimus-Eluting Stent in Coronary Lesions (SIRIUS) trial, drew a more propitious profile (almost US$27,000 for every earned QALY) than the Canadian trial. Nevertheless, both studies had some critical limitations:28
- the studies considered for the efficacy estimation did not show any advantage of survival with DES versus BMS and did not directly measure quality of life;
- studies specifically designed to estimate how many QALYs were earned by patients who received a DES were not available; therefore, all calculations to assess how many QALYs are earned using a DES instead of a BMS lack a beneficial experimental basis and represent a simulation without any robust information.
An interesting drug-economic analysis of DES versus BMS was published in 2005 by Bagust et al.,27 who obtained efficacy data from RAVEL19 and SIRIUS21 for SES and from TAXUS I, TAXUS II and TAXUS IV20 for PES. The conclusions of this study were different from those previously reported, since the drug-economic profile of DES was considered unfavourable, with the possible exception of patients with two or more risk factors. Although this paper suffers from the same limitations on QALY measurements discussed above, it is of note how the authors introduced an element of innovation when they applied the cost-effectiveness ratio. In particular, they calculated a ‘price premium’ for DES, namely the economic counterpart of clinical incremental efficacy of DES compared with BMS. The concept of price premium gives the opportunity to:
- assess the incremental benefit of DES versus BMS;
- estimate an economic equivalent for this benefit according to a pre-specified cut-off;
- calculate a ‘suggested price’ for DES as the composite of price premium and price of a BMS; and
- compare this suggested price with the real price of the device.
Thus, in their global analysis of a scenario in which 90% of patients received a DES instead of a BMS, the actual price of DES in the UK was more expensive than the recommended price with a small price premium for both SES and PES. Moreover, a further subgroup analysis showed that in only 4% of cases was the actual price balanced with the incremental benefit.
A similar criterion was adopted by Ong et al.29 to evaluate the cost-effectiveness of the unrestricted use of SES versus BMS at one and two years in the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry in Denmark.12 Interestingly, the authors analysed data pertaining to a ‘real-world’ population, estimating a neutral price of €1,023 at one year and €1,069 at two years. As the actual price of an SES in their institution in 2002 was €1,929, they concluded that the unrestricted use of SES is not cost-effective at either one and two years, and an additional shrinkage of the DES price must be strongly encouraged especially as a consequence of new DES availability with recently acquired CE certification. This increased competition together with increased market share of DES could serve to reduce the price of DES to that judged cost-effective in the decision analytic model. Correspondingly, as the market share of BMS shrinks their prices will also fall, thus necessitating that the price of DES fall even further than predicted. A new scenario is obviously desirable worldwide in which a DES will cost less than €900, thus reaching cost-neutrality. At the same time, since the results of the study of the RESEARCH registry concern a specific comparison of SES versus BMS, a new-generation DES or even a new BMS with non-polymeric coating may be responsible for a further reduction in restenosis rates, thus improving the final economic cost.
Of note, the population studied by Ong showed high-risk features, but not as high as in the Sicilian registry (e.g. 18% diabetics) or other similar studies9,12–18 of different real-world settings. Thus, since the benefit of DES is higher in patients at high risk of restenosis, the difference in cost-effectiveness of DES versus BMS could be overestimated, urging us to be cautious when we extend these findings out of their context. For example, a statistical analysis of unpublished data from the Sicilian DES registry11 with the use of decisional models reached a different result, with evidence of a substantial economic benefit of DES, especially in patients who otherwise would be candidates for CABG.
Overall, data on the cost-effectiveness of DES use in clinical practice are contrasting. All investigators must be strongly encouraged to analyse their data in light of this, verifying the pertinence of their choices. All of the following data should be taken into account for an ideal analysis:
- number of treated lesions per patient (because every treated lesion is a potential repeat revascularisation due to restenosis);
- propensity for restenosis for every treated lesion (either lesion-related or patient-related factors);
- propensity for restenosis related to the type of DES (one DES may be more effective than another DES) and BMS considered for the comparison (some DES are shown to be more effective than others);
- number of DES implanted, because the price of the device represents a considerable amount of the overall cost;
- the price of a repeat revascularisation is different if only balloon angioplasty is performed, or DES implantation or CABG;
- total cost cannot be reconciled with the reimbursement related to the DRG; and
- the economic benefit with the use of DES is a function of the procedure adopted for the comparison, e.g. PCI with BMS implantation versus CABG.
With cost-effective use of DES, physicians can pay attention entirely to technical matters, such as the pertinence of the use of drugs and devices and their clinical efficacy. This may be of great advantage for both patients and healthcare. Pending further information from RCTs, observational studies with DES will continue to supply us with both clinical and economic insights, especially when they reflect current practice in interventional cardiology.