Introduction

Peripheral artery disease (PAD) is characterized by narrowing (stenosis) or occlusion of peripheral arteries with consequent manifestation of ischemic blood flow. In the lower limbs, although asymptomatic in the most cases, PAD may manifest itself in different forms depending on whether it presents as claudication or as critical limb ischemia (CLI). Claudication is a functional manifestation, causing pain of varying intensity in the affected limb during walking. CLI may be evidenced by rest pain, skin ulcers, or, in its more advanced stages, necrosis and gangrene of the foot¹.

Epidemiological studies of PAD show highly variable results, mainly due to the different demographic characteristics and variations in the type of PAD in the tested populations. In fact, in the absence of screening programs, lower limb artery disease is systematically under-reported or mis-diagnosed. The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) reports prevalence estimates in the general population ranging between 3% and 10%. Prevalence tends to increase with age, up to approximately 20% in patients over 70 years of age. By comparison, symptomatic PAD ranges from 3% in patients with a mean age of 40 years to 6% in patients aged about 60². The prevalence data of TASC II suggest that there are around 2.7 million patients affected by asymptomatic PAD and around 1 million with symptoms of atherosclerotic vascular processes in Italy.

Clear data on PAD morbidity and mortality have been reported. Progressive worsening of prognosis over time with increased mortality and associated comorbidities is observed in patients with PAD. Patients with lower limb PAD have roughly 3-fold increase in risk of mortality and major cardiovascular events (heart attack and stroke)^3-5 compared with those without PAD. The global risk of occurrence of coronary or cerebrovascular disease exceeds 60%⁶.

The most significant complication related to CLI is amputation. Even today, this clinical consequence affects a large segment of the population (from 120,000 to 500,000 per year)⁷. It is estimated that at the time of diagnosis, 15% of patients suffering from CLI undergo primary amputation (ie, with no antecedent attempt at revascularization) and that, in the following 6 months, the risk rises to 40%⁸ Obviously, the clinical picture worsens in diabetic patients, in whom we observe a rate of lower limb amputation 20-fold higher than in the general population⁹.

PAD-related revascularizations and complications such as amputations represent a substantial and growing financial burden to health care systems¹. Notably, PAD patients are likely to generate higher healthcare costs than those with cerebrovascular or coronary artery disease¹⁰.

The optimal treatment for patients with lower limb peripheral disease (especially for disease of the superficial femoral artery) is a matter of continuing debate. Today, the available treatment options vary according to the severity of the disease. In some cases, lifestyle interventions such as smoking cessation, exercise, and diet are sufficient; in others, surgical treatment, which can proceed via a bypass operation or through a minimally invasive endovascular procedure¹¹, is chosen. In particular, standard balloon angioplasty (percutaneous transluminal angioplasty (PTA)) is an attractive minimally-invasive procedure. This can be performed with different technologies. A balloon may be used to dilate the occluded vessel (plain old balloon angioplasty (POBA)). Bare-metal stents (BMSs) may be implanted. In addition to dilating the vessel, BMSs provide structural support to avoid re-occlusion. Drug-eluting stents (DESs) which, in addition to providing structural support to the vessel, exploit the anti-proliferative actions of drugs to inhibit the process of restenosis, may be substituted^12,13. Drug-coated balloons (DCBs) are promising alternatives for the treatment of patients with PAD due to the potential reduction in re-intervention rates compared with other technologies commonly used^14-16.

This analysis had multiple objectives: i) to evaluate total costs per patient associated with each with the 4 endovascular therapies currently in use for PAD (DCBs, POBA, BMSs, and DESs) at 1 year using a decision analytic model; ii) to apply the results of the 1-year analysis to estimate the total economic impact on the Italian National Healthcare Service (NHS) for peripheral interventions over a 5-year period.

Figure 1

Structure of the decision analytic model TLR: target-lesion revascularization; POBA: plain old balloon angioplasty; DCB: drug-coated balloons; BMS: bare metal stents; DES: drug-eluting stents; s/p: status post; M: Markov states.

Methods

A budget impact model was developed to compare the relative economic results in Italy of the 4 different index procedure treatments (POBA, DCBs, BMSs and DESs) based on the repeat-procedure rates (ie, target lesion revascularization (TLR)) over 1 year. The model was developed to ascertain the specific costs to the NHS with a 5-year time horizon.The effectiveness measure used in the model was the 1-year rate of reintervention (TLR) for each of the 4 therapies of interest. The model was based on the recently published pooled estimates of Pietzsch¹⁷. The TLR values used in the model were converted to 12-month rates that were considered more realistic from the Italian NHS perspective. Costs associated with each treatment were derived from the average diagnosis-related group (DRG) tariffs used for peripheral angioplasty procedures. A decision analytic model was developed to estimate 12-month total costs of index procedures and possible revascularizations (based on pooled TLR rate estimation) covered by the NHS. The decision tree with the 4 index procedure strategies was combined with a Markov model to simulate the patient pathway for femoral-popliteal disease. Figure 1 provides the specific structure of the decision analytic model. Transition probabilities varied with the specific index procedure.

The choice of therapy used in re-interventions was based on expert opinion. In Appendix A the patient pathway considered for each index therapy is indicated according to the transition probabilities assumed. The cycle length of the Markov model was 1 week. Based on per-patient savings, total potential savings over 5 years were estimated considering 3 different scenarios of DCB adoption. Table 1 provides an overview of these scenarios, considering the current market situation and a realistic forecast for the next few years.

The model was built according to the following assumptions: i) bypass surgery was not considered as an index option, as the lesions evaluated in the analysis were not complex (consisting of Rutherford categories 2 and 3); ii) due to the lack of solid evidence comparing atherectomy with the endovascular approach, atherectomy was only considered in combination with use of another device for re-intervention purposes; iii) in the 12-month follow-up period, only 1 re-intervention after the index procedure was evaluated; iv) 80% of cases include pre-dilation via angioplasty balloon; v) only 1 device was used in each intervention, as the average lesion length was only 75 mm; vi) deaths or amputations were not accounted for.

Cost associated with each treatment (for both index procedures and possible re-interventions) were derived from the average DRG tariffs currently in use in Italy for peripheral endovascular procedures¹⁸. In particular, the tariffs for inpatient reimbursement associated with following procedures were weighted for the frequency of each DRG observed at national level: DRG 479 “Other interventions on Cardiovascular System without complications”, DRG 553 “Other interventions on Cardiovascular System with complications and without Major Cardiovascular Diagnosis”, and DRG 554 “Other interventions on Cardiovascular System with complications and without Major Cardiovascular Diagnosis”. Any additional add-on payment was included in the analysis. It is important to emphasise that, at this time in Italy, all peripheral endovascular procedures receive the same reimbursement, independent of technology used (POBA, DCBs, BMSs, or DESs). Table 2 shows all the input parameters used to populate the model.

Results

Based on a systematic literature review of clinical measures¹⁷, 12 publications including registries and clinical trials were used to estimate the TLR rates associated with each endovascular procedure studied [19-29]. More detailed information about TLR probabilities indicated in each study is shown in Table 3. Appendix B synthesizes the features of all studies included in the systematic review and used for TLR estimation.

Using a pooling weighted approach (assuming a constant hazard rate) the 12-month TLR probabilities for each index therapy were obtained. The pooled 12-month TLR rates show clear patient benefit with DCBs (6.9%) compared to POBA (21.7%) or BMSs (14.3%) and non-inferiority versus DESs (7.3%). The TLR results obtained from the pooling analysis are shown in Figure 2.

Total payments for index procedures and possible repeat interventions (based on TLR rates estimation) across all treatments suggested that DCBs were the least costly treatment strategy over a 1-year period. The average cost per patient treated with DCBs as index strategy was €6073, compared with €6095 for DESs, €6492 for BMSs, and €6914 for POBA. POBA is currently considered the standard of care for femoral-popliteal disease in Italy. Considering the NHS perspective and the total DRG payment used, DCBs showed a saving of almost €1000 per patient over 1 year. The 12-month cost-per-patient scenario is graphically presented in Figure 3.

The number-needed-to-treat (NNT) to avoid a TLR over 12 months obtained by comparison of the most effective (DCBs) to the least effective therapy (POBA) is 7. Considering the clinical non-inferiority of DCBs compared with stenting procedures (either DES or BMS) the NNT evaluation is not significant. However, it is important to emphasise that DCB offer clear benefit without any permanent implantation. Avoiding such implantations provides further clinical and procedural advantages for patient and operator, considering the hypothesis of re-intervention over the long term. Based on the above per-patient savings, the total potential savings amounted to approximately €8.7 million for an assumed annual increase of 5% in DCB adoption rate over 5 years (defined as the “optimistic” scenario). In the “pessimistic” scenario, cost-savings due to use of DCB are not fully offset due to the increased adoption of POBA over the time-frame considered in the analysis. The 5-years potential savings is graphically presented in Figure 4.

Discussion

This study investigated the economic impact in Italy of DCBs compared with other technologies currently in use for peripheral angioplasty procedures (POBA, BMSs, DESs). The results obtained from this budget impact analysis show that in patients with femoral-popliteal arterial obstructions, DCBs are the least costly treatment strategy from the NHS perspective. The analysis shows that DCBs offer improved clinical and economic outcomes compared with POBA and BMSs. By contrast, DCBs seem to offer clinical advantages and, as a consequence, economic impact similar to DES.

This analysis is based on the clinical outcome data currently available in the literature for all 4 endovascular technologies (POBA, DCBs, BMSs, and DESs) used in “de novo” lesions in the superficial femoral artery and/or popliteal artery disease and on the DRG tariffs used in Italy for endovascular procedures. Unfortunately, these results cannot be compared with similar economic evaluations performed in Italy because the economic impact of DCBs has never previously been estimated. At present, there are few studies in the literature related to peripheral endovascular interventions, ie., a cost-effectiveness analysis of DCB use in femoral-popliteal arterial obstructions performed from the facility/physician provider perspective [30]. The analysis in the present study bases the economic value of DCBs on TLR rates reported in the literature and, as a consequence, on the assumption that lower rates of re-intervention are associated with lower inpatient costs when compared with POBA, despite the greater initial investment for the technology. The analysis of Diehm et al. [30] comparing DCBs with the stenting approach concluded that the introduction of dedicated financial incentives aimed at improving DCB reimbursement may help lower total healthcare costs. The study published by Kearns et al³¹ investigated the economic impact of DCB use in populations of patients with intermittent claudication or critical limb ischemia CLI. For patients with more complex characteristics, the conclusions of the analysis favour DCBs, which, in both patient populations, represent a more cost-effective treatment option compared with the considered alternatives (PTA or bail-out BMSs). Our results are consistent with the economic evaluation of endovascular interventions recently performed by Pietzsch et al. for the US and Germany¹⁷. These authors established that drug-eluting strategies (DCBs and DESs) had lower budget impacts over 24 months when compared with the other strategy options (PTA and/or BMSs) in both the US Medicare (DCBs: $10,214; DESs: $12,904; BMSs $13,802; PTA $13,114;) and German public health care systems (DCBs €3619; DESs €3632; BMSs €4026; PTA €4290).

Figure 2

12-month TLR probabilities for POBA, DCB, BMS, and DES. TLR: target-lesion revascularization; POBA: plain old balloon angioplasty; DCB: drug-coated balloons; BMS: bare metal stents; DES: drug-eluting stents.

Figure 3

Total DRG payments per patient over 12 months POBA: plain old balloon angioplasty; DCB: drug-coated balloons; BMS: bare metal stents; DES: drug-eluting stents.

Figure 4

Total potential savings over 5 years for 3 different scenarios of DCB adoption

Our analysis has some limitations. The first is that the key assumptions on which the model is based that may preclude the generalisation of results to current clinical practice. More specifically, the present study is based on clinical evidence related only to the femoral-popliteal district, while the real focus for most specialists involved in the management of lower-limb arterial disease is the treatment of patients with CLI. Moreover, the most significant clinical evidence currently available in the literature is mainly related to less complex lesions.

There are also potential limitations in the studies included in the literature review. Comparative data across all therapies are still limited (especially randomised controlled trials), and TLR rates vary greatly between trials. As a consequence, a pooling analysis based on sample size was conducted to compare available results for each endovascular technology. Other key assumptions are related to the model hypotheses included. Bypass surgery was not considered as an index treatment option, because only lesions of moderate complexity were considered in the model. Furthermore, considering the short cycle length of the model (1 week), the hypothesis selected only 1 potential re-intervention during the 12-month follow-up. Also, the assumption that only 1 device per intervention is used is dependent on the average lesion length included (around 75 mm). Other limitations involve the annual increase of revascularization and DCB adoption rate, which are based on internal market surveys. Finally, the choice of therapy used as second intervention is based on expert panel opinion. Other transition probabilities might lead to different results in terms of economic impact.

In conclusion, we emphasize that inpatient costs for each treatment (for both index procedures and re-interventions) are derived from the average DRG tariffs currently in use in Italy for peripheral endovascular procedures, where the reimbursement status is independent of technology used. While this is correct from the NHS perspective, the stipulation highly influences the final model results. In fact, the decision analytic model suggests that DCB may be a cost-saving strategy for the national/regional payer but, using the actual hospitalization costs, may have a negative financial impact on hospital administrations. Having the same reimbursement for each technology used in peripheral procedures increases the use of DCBs (the most expensive device, but with a lower rate of re-intervention), but decreases the profit for hospitals. As a consequence, the device cost is still the most important aspect of technology choice in Italy. For this reason, we feel strongly that decision-makers should consider performing on this type of analysis and providing equal reimbursement for innovation treatments to avoid the creation of similar barriers in market access.

Another important consideration is connected to the type of costs included in the analysis. We only have considered direct costs for inpatient treatment; all other costs for the outpatient management that characterize this population were not accounted for. It is reasonable to assume that the poorer clinical outcomes observed for POBA and BMSs would lead to more outpatient costs because of the higher recurrence of symptoms. As a consequence, the total expenditure for these DCB treatment alternatives may have been underestimated by the present analysis.

This budget impact analysis addresses the current gap of information about economic aspects of DCB use in peripheral angioplasty procedures. Further studies should be carried out to compare our results with studies in other health systems to thoroughly evaluate the economic value of this innovative technology. Despite the above-mentioned limitations, this budget impact analysis suggests that DCBs may be a cost-saving strategy from the NHS perspective compared to the other technologies currently in use for PTA procedures.