Mortality Assessment of Paclitaxel-Coated Balloons: Patient-Level Meta-Analysis of the ILLUMENATE Clinical Program at 3 Years

Abstract

Background: A recent summary-level meta-analysis comprising randomized, controlled trials (RCTs) of femoropopliteal paclitaxel-coated balloon and stent intervention identified excess late mortality in the paclitaxel-treated patients.

Methods: We evaluated the safety of the Stellarex drug-coated balloon (DCB) for femoropopliteal artery disease with an independently performed meta-analysis of patient-level data from all patients in the Stellarex femoropopliteal clinical program. To compare mortality after DCB or uncoated percutaneous transluminal angioplasty (PTA), we aggregated data from 2 RCTs comprising 419 patients treated with DCB and 170 patients treated with PTA. In an additional analysis, data were aggregated from 6 poolable Stellarex DCB studies (2 RCTs, 3 single-arm studies, and 1 registry). All serious adverse events including deaths were adjudicated by a blinded, third-party, independent Clinical Events Committee. Kaplan-Meier estimates in the RCTs were compared with restricted mean survival time. Predictors of death were assessed with hazard ratios (HRs) and Cox proportional hazards modeling.

Results: Baseline characteristics were similar in the patients treated with DCB and PTA in the pooled RCT analysis, with the exception that the DCB cohort was younger (67.4±9.7 versus 69.4±9.4 years, P=0.02), smoked more frequently (86.6% versus 78.8%, P=0.02), and were less often treated for recurrent lesions (8.8% versus 14.7%, P=0.04). In the RCTs, patients treated with DCB had all-cause mortality rates that were not different from those of patients treated with PTA (Kaplan-Meier estimates 1.8±0.7% versus 1.3±0.9%, 6.5±1.2% versus 5.9±1.9%, and 9.3±1.5% versus 9.9±2.4% at 1, 2, and 3 years, respectively, P=0.86). All-cause mortality rates were similar in a 1906-patient pooled nonrandomized DCB data set (Kaplan-Meier estimates of 2.1%, 4.9%, and 7.0% at 1, 2, and 3 years, respectively). Clinical Events Committee-adjudicated causes of death were balanced between the DCB and PTA cohorts. Multivariable Cox modeling identified age (HR, 1.06; 95% CI, 1.04-1.08; P<0.001), diabetes mellitus (HR, 1.42; 95% CI, 1.01-2.00; P=0.04), congestive heart failure (HR, 1.88; 95% CI, 1.12-3.16; P=0.02), and renal insufficiency (HR, 2.00; 95% CI, 1.33-3.01; P<0.001) as predictors of mortality. Paclitaxel exposure was unrelated to mortality (HR, 1.04; 95% CI, 0.98-1.10; P=0.23).

Conclusions: The mortality rates for patients treated with the DCB and uncoated PTA were indistinguishable over 3-year follow-up. Additional patient-level, adequately powered meta-analyses with larger RCT data sets will be needed to confirm the generalizability of these findings.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110524, NCT01858363, NCT01858428, NCT03421561, NCT01912937, NCT01927068, and NCT02769273.

Keywords: mortality; paclitaxel; peripheral vascular diseases.

Figure 1.

Hazard rates for mortality for drug-coated balloon arms of the 2 randomized, controlled trials (RCTs). The Pivotal study and EU RCT had nearly identical hazard rates with an overall I² of 0.0%, indicative of homogeneity. EU RCT indicates CVI Drug-coated Balloon European Randomized Clinical Trial; and PIVOTAL, Pivotal Trial of a Novel Paclitaxel-coated Percutaneous Angioplasty Balloon.

Figure 2.

Hazard rates for mortality in patients treated with drug-coated balloons.A, The hazard rates for mortality in patients treated with drug-coated balloons (DCBs) in the 7 Stellarex studies. Patients treated with DCBs in the 7 Stellarex studies had an overall I² of 47.3%, consistent with moderate heterogeneity. ILLUMENATE PK was an outlier, with a hazard rate of 0.10. B, Annualized hazard rates for mortality for patients treated with DCBs in the 6 Stellarex studies. After elimination of the PK study, the overall I² decreased to 38.6%, reflecting moderately low heterogeneity in the 6 remaining studies. EU RCT indicates CVI Drug-coated Balloon European Randomized Clinical Trial; FIH, first in human; GLOBAL, Global Study of a Drug-coated Balloon to Treat Obstructive SFA and/or Popliteal Lesions; ISR, in-stent restenosis; PIVOTAL, Pivotal Trial of a Novel Paclitaxel-coated Percutaneous Angioplasty Balloon; PK, pharmacokinetic; RCT, randomized, controlled trial; and SAVER-E, Stellarex Vascular E-Registry.

Figure 3.

Survival in the pooled randomized, controlled trials (RCTs). The pooled RCTs show no significant differences in the survival rates in the 2 groups through 3-year (1080-day) follow-up. For further information about pooling, refer to the combining data sets section of the article. The P value tests the null hypothesis that restricted mean survival time (RSMT) for the 2 curves are equal vs the alternative that they are not equal. DCB indicates drug-coated balloon; and PTA, uncoated percutaneous transluminal angioplasty.

Figure 4.

Survival through 3 years (1080 days) in the 6-study pooled data set. The ILLUMENATE PK study (Pharmacokinetic Study of Drug-coated Angioplasty Balloons in the Superficial Femoral or Popliteal Arteries) was excluded because there were no deaths. The Kaplan–Meier estimates are reported for each year. DCB indicates drug-coated balloon.

Figure 5.

Survival through 3 years in the 4 nonrandomized, pooled studies. The 3-year mortality estimate for the ILLUMENATE FIH (CVI Drug-coated Balloon First in Human Trial), ILLUMENATE Global (Global Study of a Drug-Coated Balloon to Treat Obstructive SFA and/or Popliteal Lesions), Global-ISR (in-stent restenosis), and SAVER (Stellarex Vascular E-Registry) studies was 7.0% by Kaplan–Meier methodology. DCB indicates drug-coated balloon.