This study aimed to report the 5-year outcomes from the ILLUMENATE Pivotal randomized controlled trial of the lower dose (2 µg/mm 2 ) Stellarex drug-coated balloon (DCB) (Philips, formerly Spectranetics Corp, Colorado Springs, Colorado) compared with percutaneous transluminal angioplasty (PTA) for the treatment of symptomatic peripheral arterial disease. Long-term safety and effectiveness data for DCBs remains limited. The ILLUMENATE Pivotal was a prospective, randomized, multi-center, single-blinded study. Patients (Rutherford Clinical Category 2 to 4) were randomized 2:1 to Stellarex DCB or PTA. Follow-up was through 60 months. In total, 300 patients were enrolled. The mean age was 68.8 ± 10.2 years. At 60 months, freedom from a primary safety event was 69.2% in the Stellarex DCB arm and 68.2% in the PTA arm (log-rank, p = 0.623). The cumulative rate of major adverse events was 41.0% compared with 44.6% (p = 0.597), respectively. Freedom from clinically-driven target lesion revascularization (CD-TLR) was 70.3% in the Stellarex DCB arm compared with 68.2% in the PTA arm (p = 0.505). Time to first CD-TLR was 768.3 ± 478.9 days compared with 613.5 ± 453.4 days, respectively (p = 0.161). Kaplan-Meier estimates of freedom from all-cause mortality were 80.1% in the Stellarex DCB arm and 80.2% in the PTA arm (log-rank, p = 0.980). In conclusion, the 5-year results of the ILLUMENATE Pivotal randomized controlled trial add to the consistent safety data from the broader ILLUMENATE clinical program. These are the first data to report the 5-year safety and efficacy of a lower dose (2 µg/mm 2 ) DCB for the treatment of symptomatic peripheral arterial disease.
Clinicaltrials.gov Registration: NCT01858428
There are currently 5 drug-coated balloons (DCBs) approved for the treatment of symptomatic peripheral arterial disease (PAD) of the femoropopliteal segment. Although universally classified as DCB, each device differs by paclitaxel dose, excipient used, and pharmo-kinetics. Despite these differences in individual DCBs, the superiority of DCBs over percutaneous transluminal angioplasty (PTA) has been established at 1 year. The DCB paclitaxel dose on each device varies from 2.0 to 3.5 µg/mm 2 ; however, long-term data regarding the safety and efficacy of DCBs is only available for the higher dose (3.5 µg/mm 2 ) IN.PACT Admiral (Medtronic, Minnesota) DCB.
The lower dose (2 µg/mm 2 ) Stellarex (Philips, formerly Spectranetics Corp, Colorado Springs, Colorado) DCB consists of a polyethylene glycol excipient and a combination of amorphous and crystalline paclitaxel. The Stellarex DCB showed significantly higher primary patency relative to PTA through 36 months along with improvements in the functional status of patients treated for symptomatic femoropopliteal PAD. At 48 months, no difference was observed for freedom from CD-TLR and importantly all-cause mortality.
In the present analysis, we report the final safety and effectiveness data of the ILLUMENATE randomized controlled trial (RCT) in which patients with symptomatic femoropopliteal PAD were randomized 2:1 to treatment with the Stellarex DCB or PTA. Patients were followed through 60 months. To date, this is the first study to evaluate the long-term, 5-year safety and effectiveness outcomes of a lower dose (2 µg/mm 2 ) paclitaxel DCB for the treatment of Rutherford Clinical Category 2 to 4 femoropopliteal PAD.
Methods
The detailed population, end points, and statistical analyses have been previously published. Briefly, ILLUMENATE Pivotal (NCT01858428) was a prospective, randomized, multi-center, single-blinded study performed at 43 sites across the United States and Europe. Patients with symptomatic Rutherford Clinical Category 2 to 4 femoropopliteal PAD were randomized 2:1 to treatment with the Stellarex DCB or PTA. Institutional Review Board or local Competent Authority/Ethics Committee at each site approved the study, and written patient informed consent was obtained before study procedures were performed. Patients attended clinical visits at 6, 12, 24, and 36 months after the index procedure for clinical assessment, functional status, adverse events, medication compliance, and duplex ultrasound examination. Patency was collected at clinic visits through 36 months and was not assessed after this time point . Follow-up at 48 and 60 months was performed through telephone contact (unless the patient visited the clinic for a different reason) and included patient-reported medication compliance and adverse events.
The primary safety end point was a composite of freedom from device-related and procedure-related death through 30 days and freedom from CD-TLR through 12 months. CD-TLR was defined as reintervention of the target lesion for diameter stenosis >50% by angiography, and Rutherford Clinical Category increase >1 or ankle-brachial index decrease >0.15. The primary effectiveness end point was primary patency (defined as the absence of target lesion restenosis by duplex ultrasound [peak systolic velocity ratio ≤2.5] and freedom from CD-TLR) at 12 months. Primary end points were previously published as were additional outcomes through 4 years. , Per protocol, follow-up continued through 60 months.
The 60-month outcomes collected and reported in this study include mortality, the composite safety end point, and major adverse events (MAEs). The composite safety end point was defined as freedom from device-related and procedure-related death through 30 days postprocedure and freedom from target limb major amputation and CD-TLR through 60 months. The MAE rate was defined as a composite of cardiovascular death, target limb major amputation, and CD-TLR through 60 months. The individual components of the MAE composite were also collected; and, in those patients experiencing a CD-TLR, time to CD-TLR was recorded.
All data were 100% source verified. An independent, blinded Clinical Events Committee adjudicated all adverse events, including mortality. An independent Data Safety and Monitoring Board monitored safety.
Outcomes are reported for the intent-to-treat population (i.e., all patients enrolled by the assigned treatment according to randomization), with the exception of all-cause and cardiovascular mortality which were collected on the retrospectively obtained vital status cohort. The vital status cohort included the intent-to-treat population and patients who formally exited the study. Patient vital status was ascertained through 60-month follow-up. As the patients in the vital status cohort consisted of those who formally exited the study, only vital status was obtained.
Detailed methods of the statistical analyses were previously described. , Mean days to the first CD-TLR between treatment arms were compared using a t test. Kaplan-Meier (KM) time-to-event methodology was used to assess freedom from the primary safety event, freedom from CD-TLR, freedom from all-cause mortality, and freedom from cardiovascular mortality through 60 months. The log-rank test was used to assess differences between groups. For analysis of the safety end point, subjects failing any component were considered a safety failure, and subjects who remained event-free through the study visit were considered safety successes. Data were analyzed with SAS version 9.3 or higher (SAS Institute Inc., Cary, North Carolina). A p Value of <0.05 was considered statistically significant. Nominal p values are reported with no adjustment for multiplicity.
Results
The ILLUMENATE Pivotal RCT enrolled 300 patients at 43 study sites in the United States and Europe. Of these, 200 were randomized to the Stellarex DCB and 100 to PTA. Baseline and procedural characteristics were described previously and are summarized in Supplementary Tables 1 and 2 . Briefly, the mean age was 68.8 ± 10.2 years; and, the study included a complex cohort of patients as shown by high rates of hypertension (93.7%), obesity (36.3%), diabetes (50.3%), severe calcification (43.6%), and female patients (41.3%). Mean lesion length was 8.0 ± 4.5 cm in the Stellarex DCB compared with 8.9 ± 4.6 cm in the PTA arm. Most lesions were in the mid SFA (50.5% Stellarex DCB; 49.0% PTA), followed by the distal SFA (34.0% Stellarex DCB; 32.0% PTA), proximal SFA (10.5% Stellarex DCB; 9.0% PTA), proximal popliteal (4.0% Stellarex DCB; 8.0% PTA), and mid popliteal (1.0% Stellarex DCB; 2.0% PTA). The mean reference vessel diameter was smaller (DCB 4.9 mm versus PTA 5.2 mm, p = 0.017) and there were fewer restenotic lesions (DCB 9.5% versus PTA 18.0%; p = 0.035) in the Stellarex DCB arm. There were no other significant differences in the baseline and procedural characteristics between the 2 study cohorts.
The median follow-up in the Stellarex DCB arm was 4.9 years (IQR 4.1, 5.0) compared with 4.9 years (IQR 4.2, 5.0) in the PTA arm. Patient enrollment and follow-up through 60 months are shown in Figure 1 . Upon completion of the ILLUMENATE Pivotal RCT, 99.3% of DCB patients and 100% of PTA patients completed the 60-month visit. The 60-month in-window follow-up visit compliance was 95.6% (96.3% for the DCB group and 94.3% for the PTA group).
KM estimates of freedom from the composite safety event were 69.2% in patients treated with the Stellarex DCB and 68.2% in patients treated with PTA (log-rank, p = 0.623) ( Figure 2 ). Table 1 lists MAEs through the 60-month follow-up period. The MAE rate was 41.0% (64/156) in patients treated with the Stellarex DCB compared with 44.6% (37/83) in patients treated with PTA (p = 0.597). The individual components of the MAE composite were similar between the 2 cohorts ( Table 1 ). Throughout the 60-month study window, there were 2/137 (1.5%) target limb major amputations reported in the Stellarex DCB arm and 0/67 (0.0%) reported in the PTA arm, with no statistically significant difference between the groups (p = 1.000). One patient received an above-the-knee major amputation 1,323 days after the index procedure because of progressive gangrene of the left leg and the other patient had a below-the-knee major amputation of the right leg 589 days after the index procedure because of a nonhealing ulcer on the ipsilateral foot. Notably, the 2 major amputations that occurred in the Stellarex DCB cohort were determined by the Clinical Events Committee to be unrelated to the device or procedure.
