The aim of this study was to assess the long-term mortality of patients treated by the IN.PACT Admiral (Medtronic, Dublin, Ireland) paclitaxel-coated balloon angioplasty (PCBA) compared with standard plain balloon angioplasty (POBA).
Materials and Methods
Between January 2013 and January 2014, 238 patients met the inclusion criteria. A two-step analysis was performed. In step 1, the 5-year mortality of the whole patient population was evaluated regardless of possible differences in the patient demographics. In step 2, a matched paired analysis was performed using propensity scores. In addition, for those patients who were treated with PCBA, a possible correlation between dose of paclitaxel and mortality was evaluated.
Univariate analysis for the whole group of patients (POBA group A, n = 84 and PCBA group B, n = 121) showed a 5-year mortality rate of 26.2% versus 14.0%, p = 0.02, respectively. Univariate analysis of 77 pairs of propensity score-matched patients resulted in mortality of 26.0% versus 20.8%, p = 0.4, of group A and B, respectively (median follow-up of 61.7 and 61.8 months, p = 0.8, respectively). Comparison of the patients of group B who died versus those who survived showed no correlation between the dose of paclitaxel with increased mortality (p = 0.4).
The 5-year findings of the present real-world study showed no increased mortality for the matched patients who underwent PCBA versus POBA. In addition, there was no correlation between mortality and the dose of paclitaxel used.
Several randomized controlled studies have already demonstrated strong evidence regarding the clinical utility of the use of paclitaxel-coated technologies for patients with failed conservative treatment and persistent intermittent claudication [1,2,3,4,5]. A systematic review and meta-analysis of 28 randomized trials of paclitaxel-coated devices concluded recently that there is an increased risk of all-cause death at 2 and especially at 5 years following application of paclitaxel-coated balloons and stents . Although this meta-analysis was well conducted and the statistical analysis was sophisticated in minimizing heterogeneity in the included series, several limitations were reported creating a remarkable ambiguity in the final conclusion. In detail, only 2 of the overall 28 trials reached the 5-year time point, leading to a significant number of patients lost to follow-up. Furthermore, the studies were conducted based on an intention-to-treat analysis without the possibility to detect a “true paclitaxel exposure” due to the substantial number of patients who crossed over to the alternative treatment arm. No patient-level data were included between those who died and those who did not. Finally, and most importantly, no clear causal relationship between exposure to paclitaxel and mortality was found. Despite the mentioned limitations, the Katsanos meta-analysis  raised major concerns about the safety of drug-eluting devices, and several ongoing multicenter randomized trials using paclitaxel-coated balloons and stents stopped further recruitment of patients. Consequently, a major scientific need exists to assess whether the unexpected findings of the Katsanos meta-analysis may be reproduced in broad real-world clinical studies . The aim of our study was to take a deeper look at this issue and focus on the long-term mortality of all-comer real-world patients treated at our institution by paclitaxel-coated (PCBA) versus plain old balloon angioplasty (POBA).
This was a single-center, retrospective analysis of prospectively collected data, performed in line with the requirements of the local ethics committee and adhering to the Declaration of Helsinki. All patients consented to the procedure prior to the intervention. The study was an investigator-driven initiative performed without any financial support from the industry. Between January 2013 and January 2014, the clinical records of all patients in Rutherford category III who underwent endovascular treatment of a de novo femoropopliteal lesion at our center were included in this study. Patients with in-stent restenosis, concomitant severe (> 50%) common femoral artery stenosis, stenosis of a bypass anastomosis and iliac or infrapopliteal occlusive disease with involvement of the crural arteries were excluded from the analysis.
All patients underwent a thorough clinical examination at baseline. Patient demographics and comorbidities, as well as imaging and clinical data, were prospectively collected and retrospectively analyzed. Follow-up clinical examinations were scheduled at 6 and 12 months after the initial procedure. The patency of the treated vessels was assessed using duplex ultrasound at each follow-up visit. In cases of symptomatic worsening, angiography was recommended.
Dual-antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day) was routinely prescribed for 3 months, followed by lifelong aspirin or clopidogrel monotherapy. Patients previously taking warfarin or oral anticoagulant agents were maintained on the anticoagulant agents with additional clopidogrel therapy for 3 months after the procedure. Patients with aspirin allergies received only lifelong clopidogrel.
The selection of the treatment option was left completely to the discretion of the responsible physician. In cases where paclitaxel-coated balloons were used, vessel preparation was mandated using an uncoated balloon catheter inflated to a diameter of 1 mm less than the reference vessel diameter. The inflation time is standardized at our institution (60 s).  Subsequently, the paclitaxel-coated balloon was selected based on the reference vessel diameter and inflated for 180 s. In cases of a flow-limiting dissection confirmed at 2 projections or residual stenosis > 50%, adjunctive implantation of a nitinol stent (ev3 Protégé, Medtronic, Santa Rosa, USA) was performed from healthy-to-healthy segment of the vessel. The maximum overlap between two stents was 1 cm. The stents were dilated after deployment using a standard uncoated balloon catheter to achieve its reference diameter.
Data were extracted from the clinical charts and the ORBIS system (Agfa Healthcare, Bonn, Germany) which included baseline patient demographics, prescribed antiplatelet therapy, procedural variables, length and diameters of the devices used and outcome data on patient mortality during different time periods. In the case of loss to follow-up, the patients and their local doctors were contacted by telephone and mail to complete a survey.
The outcome measurement of the study was death from any cause. All-cause death was analyzed at different time points following conventional or paclitaxel-coated balloon and/or stent angioplasty of the leg.
In all drug-coating balloon (DCB) cases, the device used was the IN.PACT™ Admiral™ DCB (Medtronic Vascular, Santa Clara, CA, USA). The FreePac™ drug coating on the balloon of the IN.PACT Admiral DCB consists of the drug paclitaxel and the excipient urea. The balloon surface has a nominal paclitaxel dose density of 3.5 μg/mm. The total administered dose of paclitaxel was calculated as balloon area ×3.5 μg/mm. The balloon area (in mm2) was calculated as 2πR × balloon length (π = 3.14, R = balloon diameter/2).
All continuous data were not normally distributed and presented as median and interquartile range (IQR) or in variables with a small number of subjects as median and minimum–maximum. Univariate analysis of continuous data was made by the nonparametric Mann–Whitney U test, while categorical data presented as n and percentage were compared with Pearson’s Chi-square test, as appropriate. The observed follow-up mortality was significantly higher in the POBA subgroup of included patients. These patients showed a higher prevalence of well-established comorbid conditions. A two-step analysis was performed. In step 1, the 5-year mortality of the whole patient population was evaluated regardless of possible differences in the patient demographics. In step 2, a matched paired analysis was performed using propensity scores. In addition, for those patients who were treated with PCBA, a possible correlation between dose of paclitaxel and mortality was evaluated. Data were analyzed using SPSS 22.0 (IBM, Armonk, NY, USA).
The patients were classified into group A (n = 113) for those who had undergone POBA and group B (n = 125) for those who had undergone PCBA. Figure 1 shows a flowchart with the criteria and the number of the included patients of the two groups. Univariate analysis for the patients of groups A and B showed a 5-year mortality of 21.2% versus 14.0%, p = 0.06, respectively. Twenty-four patients from group A underwent a reintervention with use of paclitaxel-coated balloon during the follow-up, and five patients were lost to follow-up.
Finally, in the 5-year follow-up, 84 patients in group A had a 5-year mortality of 26.2%, compared to 14.0% for those in group B (n = 121, excluding four patients lost to follow-up), p = 0.02. On univariate analysis, the age (p < 0.001), the incidence of nicotine abuse (p = 0.02) and renal insufficiency (p = 0.002) were statistically significantly different between these two groups.
Analysis in 144 propensity score-matched patients, 77 for each group, resulted in mortality of 26.0% versus 20.8%, p = 0.4, for groups A and B (median follow-up of 61.7 and 61.8 months, p = 0.8, respectively) (Table 1). Eight patients from group A and seven patients from group B died due to cardiovascular reasons, 2 from each group due to cancer, 3 from group A and 2 from group B due to pulmonary/infectious causes, and 7 from group A and 5 from group B due to unknown reasons. Evaluation of the dose of paclitaxel in group B between the patients who died versus those who survived showed no correlation of the dose of paclitaxel with increased mortality, p = 0.4 (Table 2).
The 5-year findings of the present real-world cohort of patients treated by PCBA showed no increased mortality in the long term compared to the group of patients treated by POBA. Our study included only patients with a “benign” stage of peripheral arterial disease (Rutherford stage III), and only 6% of the included patients were lost to follow-up. In all cases, we used the paclitaxel-coated balloon with the highest dose of paclitaxel, such as the IN.PACT balloon. This is in contrast to the Katsanos meta-analysis, where the risk of death was significantly higher especially in the 3.5 µg paclitaxel/mm2 devices (like the IN.PACT balloon) compared to the lower-dose devices .
Evaluation of the clinical charts offered patient-level data of paclitaxel and provided information about the lengths and diameters of the paclitaxel-coated balloons used. The dose of paclitaxel between the patients who died versus those who survived showed no correlation of the dose of paclitaxel with increased mortality. The findings of the present study fill a gap in the research by providing novel evidence on the relative difference between these competing devices in real-world patients. Fanelli et al.  recently suggested focusing on long-term clinical events from broadly unselected real-world data treated with these devices, and to our knowledge, this is the first report on long-term clinical data regarding the mortality of consecutive patients treated by PCBA. Our data are also in alignment with a recently published independent patient-level meta-analysis which showed that the mortality is not correlated with paclitaxel exposure [9, 10].
Due to our institutional standardized clinical follow-up protocol, we were also able to detect the POBA patients who crossover to the opposite PCBA treatment arm due to use of paclitaxel-coated balloons in reinterventions. Moreover, we performed a propensity score analysis according to the demographics and comorbidity factors to identify homogeneous groups between the two cohorts. This statistical matching technique reflects the probability for an outcome (death) of a patient being assigned to a particular treatment given a set of observed covariates that may predict or affect the outcome (age, renal insufficiency, smoking). This model, which significantly reduces selection bias by equating groups based on main covariates, resulted in comparable incidence of mortality for the two groups of the treated patients. Moreover, we were able to note the administration of possible medications, such as clopidogrel and statin, which are linked to improvement in life expectancy (Tables 1 and 2) [11, 12]. Conversely, patients in randomized clinical trials are always classified based on the intention-to-treat principle without the possibility to evaluate crossover cases. Moreover, a few studies had a numerically greater incidence of patient comorbidities—smoking, hyperlipidemia, hypertension or diabetes mellitus—which influence the survival of the patients, as detailed for example in the ZILVER PTX study .
Limitations of our study represent the retrospective design and inclusion of patients treated in the year 2013 with one particular paclitaxel-coated balloon (IN.PACT Admiral). However, the retrospective evaluation of real-world data seems to be the only realistic possibility to evaluate the association of paclitaxel and mortality nowadays, because in conducting prospective randomized trials there are ethical issues regarding the selection of the comparator, the information being communicated to the patient and the current restrictions for use of paclitaxel from the FDA. The need to have a sophisticated evaluation of homogeneous groups of patients led to exclusion of some patients, resulting ultimately in having almost 150 patients for analysis of the mortality rate. This number of included patients can be underpowered for the statistical analysis, especially when the endpoint of the study is the risk of death. Finally, unfortunately, we were unable to retrospectively identify all actual causes of death in the deceased patients and subsequently identify potential causal links with paclitaxel use.
In summary, the 5-year findings of the present real-world study showed no increased mortality for the matched patients who underwent PCBA versus POBA. There was no correlation between mortality and dose of paclitaxel. Further investigations of real-world data are warranted.
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Donas, K.P., Sohr, A., Pitoulias, G.A. et al. Long-Term Mortality of Matched Patients with Intermittent Claudication Treated by High-Dose Paclitaxel-Coated Balloon Versus Plain Balloon Angioplasty: A Real-World Study. Cardiovasc Intervent Radiol 43, 2–7 (2020). https://doi.org/10.1007/s00270-019-02329-z
- Drug coated balloon angioplasty
- Real-world study
- Plain balloon angioplasty