Commentary: Role of Self-Expanding Stents in Infrapopliteal Artery Disease

Infrapopliteal disease is an important part of the spectrum of peripheral artery diseases (PAD). Generally occurring in diabetics, the elderly, or patients with chronic kidney disease (CKD), this entity is typically characterized by diffuse, multilevel involvement of the infrapopliteal arterial bed, which makes endovascular revascularization challenging in these patients. ¹ Critical limb ischemia (CLI) represents end-stage PAD with ischemic rest pain and nonhealing ischemic ulcers. Experts recommend revascularization of this segment after adequate treatment of inflow vessels (aortoiliac and/or femoropopliteal segments) and then only if symptoms remain clinically significant. ¹ Currently, it is unclear if percutaneous transluminal angioplasty (PTA) alone should be used in this vascular bed or if other interventions, such as balloon-expandable stents, self-expanding stents, or atherectomy, should be employed. The efforts of Schulte et al ² in the EXPAND trial, therefore, are a welcome addition to our knowledge base in this regard.

The EXPAND trial was a prospective, multicenter, randomized control trial (RCT) that randomized 92 patients 1:1 to either primary self-expanding stent implantation or PTA with bailout stenting. ² Astron Pulsar/Pulsar-18 stents (Biotronik AG, Buelach, Switzerland) were used, and only one lesion per patient was treated. Primary outcome was sustained clinical improvement at 12 months defined as ≥1-category improvement in Rutherford category 3 patients and ≥2-category improvement for patients in Rutherford categories 4/5 as compared with baseline. The trial found no statistical difference in this endpoint between primary self-expanding stent placement to PTA with bailout stenting at 1 year (74.3% vs 68.6%, respectively), with no statistically significant difference in mortality, limb amputation, or freedom from target lesion revascularization (TLR).

The relative paucity of literature about self-expanding stents in this patient population must be emphasized. Previous literature has primarily focused on the use of balloon-expandable stents, whether bare metal (BMS) or drug-eluting (DES), in the infrapopliteal arteries. Registry level data for the Xpert self-expanding stent (Abbott Vascular, Inc, Redwood City, CA, USA) showed rates for TLR and amputation-free survival comparable to those observed in the EXPAND trial (70.1% and 78.3%, respectively). ³ Among RCTs using BMS, Brodmann et al ⁴ found no statistically significant advantage for primary stenting with regard to improvement in Rutherford class, ulcer healing, or freedom from restenosis at 12 months; instead, they actually found a trend toward better outcomes for PTA alone. Similarly, InPeria I and II failed to show any difference in rates of amputation or clinical improvement (for InPeria II only) at 6 and 9 months, respectively.^5,6 Furthermore, Randon et al, ⁷ who used both balloon-expandable and self-expanding stents, did not find any significant advantage for primary stenting with regard to limb salvage, primary patency, or patient survival.

Trials for balloon-expandable DES demonstrated improved patency rates as compared with controls (BMS or PTA),^8-10 though significant differences in survival or improvement in Rutherford scores may not be present. ¹¹ Other technologies, such as drug-eluting balloons (DEB), have still to establish their utility in the infrapopliteal arteries. Despite showing initial promise in small trials,^12,13 the IN.PACT DEEP failed to establish superiority to PTA and actually showed an area for concern due to increased rates of major amputation in the DEB arm. ¹⁴

The EXPAND trial therefore adds to the knowledge base regarding the optimal treatment strategy for infrapopliteal lesions. There are several challenges inherent in the patient population that the trial seeks to study. Patients with predominantly infrapopliteal disease frequently have multilevel, multivessel involvement, multiple comorbidities, and fairly advanced disease in the spectrum of CLI. Frequently advanced in age, these multicomorbid patients consequently are poor surgical candidates. ¹ Furthermore, optimal endpoints to evaluate outcomes are still not well established. Most trials target freedom from TLR or restenosis/lumen loss among the primary endpoints; however, frequently these do not correlate with the clinical improvement observed in patients. Consequently, many trials for stent technologies have shown improvement in the above primary outcomes but do not show any difference in amputation, limb salvage, or ulcer healing rates or improvement in Rutherford category.

Restenosis should not, however, be treated lightly as it may be the harbinger for recurrent CLI. The clinical dictum has been that the limb requires better blood flow during the initial ulcer healing phase than maintenance of tissue integrity in the long run; hence, subsequent restenosis did not always predict recurrence of ischemic ulcerations. This view was challenged by Jaffery et al ¹⁵ in their small retrospective study of patients who had undergone TLR after initial 60-day post PTA ± stent success with abeyance of rest pain and ulcer healing. They found that 5 of 6 patients who developed restenosis progressing clinically to CLI required further intervention. Hence, the optimal durability of infrapopliteal interventions remains to be defined.

The EXPAND trial had its share of limitations as well. The targeted sample size was not reached; however, this is a frequent problem in studies regarding endovascular interventions for infrapopliteal CLI. We hope that if common outcome definitions can be obtained, a good portion of published data could be combined into a patient level meta-analysis to help us further understand the role of these interventions in infrapopliteal PAD.

Furthermore, it was noted that baseline ankle-brachial indexes of this study population were higher than what would be expected in cases with higher Rutherford categories. Every patient had only one vessel revascularized, and it is known that infrapopliteal disease frequently has multivessel involvement. It would have been useful to know about the severity of disease in the other vessels to gain a better understanding of the patient population.

Low angiographic follow-up is a frequent challenge in these studies, as angiography adds useful information about restenosis rates beyond duplex ultrasonography. Lesion length was in the intermediate range compared to previous studies in the infrapopliteal group, which is not a significant limitation, though performance of these stents in longer lesions remains undefined. Finally, it is unclear how robust the medical therapy was for these patients. Laird’s group ¹⁶ has shown that optimal medical therapy significantly improves limb salvage rates.

Ultimately, the EXPAND trial adds significant information to the literature regarding the methods of treatment for CLI. Furthermore, this information also provides natural history data to an exceptionally complex patient population and raises interesting questions for further research to define the role of stents in infrapopliteal disease.