Why Drug-Eluting Stents May Not Work for Most Patients with Leg Ischemia Caused by Below-Knee Arterial Occlusive Disease

Although the use of stents is common in other peripheral vessels, the application of stents remains highly controversial in the infrapopliteal bed (BTK). In general, infrapopliteal stent implantation is reserved for cases with a suboptimal outcome after PTA (i.e., > 50% residual stenosis, flow-limiting dissection). The fear that early thrombosis and late luminal loss due to intimal hyperplasia may lead to suboptimal long-term patency rates explains the reluctance on implanting stents in these small-diameter vessels. In the effort to optimize stent outcomes, coronary drug-eluting stent (DES) technologies have been applied to the infrapopliteal vascular bed. Feiring et al were the first to demonstrate the safety and utility of using coronary DES devices in the tibial vessels, paving the way for more widespread application in the treating of infrapopliteal disease.¹ Based on the outcome of 4 independent investigator-initiated studies, the Cypher sirolimus-eluting stent (SES) (Cordis Corporation, Miami Lakes, Florida) has been CE-marked for the BTK indication.^2–5 Our own study published in 2006 evaluating the Cypher stent for BTK application in 18 CLI patients (Rutherford category 4 and 5), resulted in a 6-month limb salvage rate of 94.4%, with an angiographic late lumen loss of only 0.38 mm in the surviving patients.⁴ Commeau et al used SES to treat 30 consecutive patients with CLI, (Rutherford category 3 to 6) and a minimum of 2 diseased infrapopliteal vessels. A limb salvage rate of 100% was achieved at a mean follow-up of 7.7 months, and all surviving patients treated with Cypher stents had marked clinical improvement, with 97% primary patency as measured by target lesion revascularization.⁵ Siablis et al compared the outcome of 29 CLI patients treated with the sirolimus-eluting Cypher stent with another 29 CLI patients receiving a bare-metal stent (BMS) for infrapopliteal revascularization. The 6-month primary patency rate was significantly higher in the Cypher group compared to the BMS group (92.0% and 68.1%, respectively, 50% restenosis of 77.4%. The 1-year incidence of clinically driven repeat interventions was 30.5%. From their first experience with infrapopliteal PES, they concluded to have reached acceptable clinical results, even though PES implantation failed to inhibit vascular restenosis and decrease the need for repeat interventions.⁷

The published high mid-term primary patency and limb salvages rates of these single-center experiences^3–5,7 suggest that the infrapopliteal implantation of SES might be beneficial for CLI patients. This might be the case if, indeed, all patients with CLI presented with lesions as short as those in the listed publications. In three^2–4 out of the four above-mentioned SES studies, inclusion criteria were limited to patients that could intentionally be treated with one coronary SES, being 30 mm in length. From our personal experience, we have learned that the majority of CLI cases referred for infrapopliteal revascularization do present with far longer lesions and far more complex disease than patients included in infrapopliteal studies. For those with focal infrapopliteal lesions, in which the full lesion length can be covered by one single DES, there will be a full DES effect on the total treated area. In longer lesions, the full length of the lesion will be predilated with a long low-pressure balloon, after which, spot-stenting will be considered for areas with residual flow-limiting stenosis or dissection. This means that if a DES stent is used for PTA optimization, the effect of the active coating is limited to the stented portion, and it will not have any effect on the lesion treated with PTA alone. The long-term vessel patency in such cases is going to be determined largely by the fate of the longer segments treated with PTA alone, and we know that this patency is likely to be considerably lower than the published DES outcomes. The coronary DES trials have taught us another important lesson: inadequate lesion coverage may contribute to the development of edge stenosis (or restenosis), negatively impacting the SES efficacy. A quantitative intravascular ultrasound (IVUS) analysis from the Sirolimus-Eluting Stent in Coronary Lesions (SIRIUS) trial demonstrated a larger percentage of uncovered plaque area at the reference segment in SES population presenting with edge stenosis 8 months after index intervention.⁸

Consequently, in the typical CLI patient presenting with long, diffuse infrapopliteal lesion, an optimal DES effect can only be achieved if the full length of the index lesion is covered with DES. Adhering to such a strategy would require use of multiple DES devices in the majority of patients. This would have, of course, an obvious and severe impact on the cost of the procedure. In the publication of Commeau et al, which describes his experience with direct stenting with SES in the infrapopliteal bed, there were no restrictions in terms of the number of SES implanted or in the maximum-allowed lesion length. They reported on the use of 106 SES stents in only 30 patients. This means an average of 3.5 SES per patient, with even one patient that received 13 stents.⁵ This undoubtedly creates an inevitable price issue: can the gained patency ever justify the increased treatment costs? Another concern with using DES in the infrapopliteal arteries is the delayed endothelialization around the stent struts as seen in coronaries, which makes the stent more susceptible to thrombosis. Despite the fact that DES thrombosis in the peripheral circulation has not had the lethal consequences seen in the coronaries arteries, use of dual antiplatelet therapy after DES is also warranted for peripheral arterial occlusive disease to enhance stent performance. Nevertheless, the use of dual antiplatelet therapy is associated with an increased incidence (1–2% per annum) of major bleeding complications and is expensive.^9,10 The duration of treatment with dual antiplatelet therapy after both coronary and peripheral implantation of DES remains a subject of ongoing debate.

Based on emerging evidence, many cardiologists are recommending a minimum of 12 months of aspirin and clopidogrel, but some are advocating indefinite use of dual antiplatelet therapy after DES implantation.¹¹ One year of clopidogrel costs approximately $1,000. This expense is in addition to the cost already incurred by using a DES, which is about four times that of the bare-metal equivalent; one coronary BMS costs $800, while one DES costs up to $2,500.¹²

Acknowledgement

The authors take great pleasure in thanking the staff of Flanders Medical Research Program, with special regards to Dr. Koen De Meester for performing the systematic review of the literature and providing substantial support to the writing of the article.