PAD affects the lower extremities and is associated with functional decline, reduced quality of life, increased depression, and increased cardiovascular morbidity and mortality . Repeat treatment for PAD is also costly, inconvenient, and associated with procedural risks. As population management becomes more important, the balance between upfront procedural cost and the cost of caring for the patient in an “extended episode of care” becomes more important. The results of the data analysis identified that certain traditional risk factors commonly thought to influence reintervention rates did not have an impact, but other clinical and anatomic variables did affect the risk of TLR after DES placement.
The present study with an aggregated data analysis of 2227 patients with femoropopliteal PAD treated with the DES is the largest to date that examines the outcomes of a drug-based endovascular device according to the presence of patient and lesion risk factors. An analysis of the impact of these risk factors on ffTLR through 5 years of follow-up allowed creation of a prediction model. This prediction model provides a risk profile for individual patients that should markedly improve risk assessment for TLR over standard clinical variables. This model can help facilitate discussions between physicians and patients with PAD regarding expected outcomes with this DES therapy. More generally, it may contribute to improving the cost-effectiveness of care by allowing vascular specialists to optimize patient selection for DES treatment.
As anticipated, there is some variability in the frequency of individual factors between studies. In some instances, this is most likely due to differences in study enrollment criteria. For example, the Japan PMS and SAS studies enrolled longer lesions, which is reflective of the studies not excluding lesions based on length. In contrast, the other three studies limited enrollment to a maximum lesion length of 140 mm. Smoking status, hypercholesterolemia (relatively low in the China study), and prior interventions were more frequent in the Japan PMS and SAS studies. Patients with ISR were enrolled in the Japan PMS and SAS studies in contrast to the other three studies where patients with prior stent placement were excluded. Inclusion of longer lesions and ISR strengthens the validity of the model predictions across a diverse patient population that is representative of patients commonly treated in clinical practice.
In both the univariate and multivariate analyses, the factors that were identified as significant were expected predictors of TLR including gender, age, CLI, lesion length, RVD, total occlusion, and prior interventions which includes ISR. Recent publication of 3-year results of DCB found similar risk of TLR including lesion length, RVD ≤ 4.5 mm, ISR, bilateral disease, CLI, and hyperlipidemia . Although popliteal involvement and smoking were significant in the univariate analysis, these factors were no longer significant when adjusting for other risk factors. A strong correlation between popliteal involvement and RVD is expected, and when including both in the model, RVD remained significant. This finding is consistent with observations from DCB . The frequency of a RVD > 5 mm was more common in the Japan PMS and SAS studies. It is possible that the differences reflect regional variations in the use of intravascular ultrasound (IVUS) rather than conventional angiography to determine vessel size. Reliance on IVUS for definitive determination of RVD is a common practice and deemed a more accurate representation of true vessel size than the traditional depiction of only the lumen provided by conventional arteriography . A study from Japan found a significantly higher rate of freedom from reintervention through 5 years when IVUS was used compared to non-use of IVUS .
There were several factors that are thought to be significant predictors of TLR; however, in this model, these factors were not significant predictors for TLR of the DES. The presence of renal disease and the number of standard tibial runoff arteries, traditionally believed to negatively impact ffTLR, did not show a significant impact in the presence of other factors included in the model. These unanticipated results are in agreement with what has been previously reported for the DES [20, 21]. While diabetes mellitus is commonly considered a risk factor for TLR following standard PTA and BMS, in this analysis diabetes did not have a significant impact, a finding previously reported in analyses of DES .
Patient age had a significant impact on TLR but in an unanticipated way. In this analysis, there was a decreasing risk of TLR as age increased. Although this may be counterintuitive initially, there are some possible explanations for this effect. Patients in the older age group may not be as ambulatory as younger patients. If patients are sedentary, they may not experience claudication or pain associated with exercise. In addition, older individuals in general have more medical comorbidities and may not be considered good candidates for reintervention. Although the finding was for restenosis and not TLR, analysis of the bare metal Supera stent showed an increased risk of restenosis through 3 years for patients < 75 years old compared to patients > 75 years old . This finding is consistent with the results for age from the prediction model in which older patients had a decreased risk of TLR.
This prediction model has been adapted into an online application for clinical use by physicians (https://cooksfa.z13.web.core.windows.net). Using a patient’s unique risk profile, which is based on the patient’s personal clinical and lesion characteristics, the calculator predicts the risk of TLR over time. The calculator can help guide patient selection for DES placement by estimating individual risk of TLR through 5 years following SFA treatment with DES. In this study, three representative patient profiles with commonly observed patient and lesion characteristics demonstrated the functionality of this approach. In addition, this may stimulate similar modeling efforts focused on other endovascular devices with data from clinical trial experience that provides long-term follow-up. Such studies may help the field define an optimal treatment algorithm for custom management of an individual with symptomatic SFA PAD and lead to evidence-based guidance focused on maximizing the benefits and cost effectiveness of intervention.
The study and the prediction model are associated with inherent limitations. Not all of the studies have 5-year follow-up (three out of five studies with 5-year results). Incomplete data collection of all factors in this analysis was minimal, resulting in approximately 6% of patient cases being omitted from the analysis. The omitted cases had a higher proportion of patients with an RVD ≥ 5 mm. These patients would be expected to have a higher ffTLR rate than those patients with smaller RVDs; therefore, the model may potentially underestimate ffTLR. Other patient characteristics were not eligible for inclusion because data for these factors were not collected in each of the five studies, including the precise type of diabetes, pulmonary dysfunction, and prior myocardial infarction. In addition, core lab analysis provides the best available data for evaluation of most anatomic factors; however, a core lab was not utilized in all studies. Accounting for all other factors in the model, the proportionality assumption was not met for two of the seven lesion length groups. Both lesion groups have considerable numbers of patients from the Japan PMS study (> 45% of the 150–199 mm lesion length group and almost all of the ≥ 300 mm lesion length group). The authors speculate that this, along with the uniqueness of the ≥ 300 mm lesion length group, could contribute to the assumption not being met. Violation of this assumption suggests that a more complex relationship than what is currently presented may be relevant for this small subset of patients. Overall, because the study outcomes and prediction model are derived from a post hoc patient-level pooled analysis from five prospective clinical trials, the present results should be considered hypothesis generating.
In summary, this study evaluates a drug-based endovascular device used for management of SFA PAD and the factors that predict ffTLR for the DES. The study uses an extensive dataset to develop the first prediction model which estimates the influence of patient and lesion characteristics on ffTLR through 5 years. Based on a unique patient profile, the model provides expected patient outcomes following treatment with the Zilver PTX DES. The results from this prediction model may assist physicians to define treatment algorithms for patients as population management grows in focus.