Meta-analysis links PCBs to increase in death and amputation
In a new meta-analysis of randomized controlled trials, the application of paclitaxel-coated balloons (PCBs) for the treatment of critical limb ischemia (CLI) below the knee was associated with a significant reduction in target lesion revascularization (TLR), but at the cost of a significant increase in all-cause death and major amputation.1
“There was good evidence from 8 RCTs that paclitaxel caused a significant reduction of TLR (ie, need to re-intervene) by approximately 40% with a number needed to benefit of 8 patients,” wrote Konstantinos Katsanos, MD, MSc, PhD (Patras University Hospital, Rion, Greece), and colleagues.
“However, contrary to the TLR benefit, there was also homogenous evidence that [amputation-free survival, AFS] was significantly lower in cases with PCBs with a >50% higher hazard of AFS loss though the first year and a corresponding number needed to harm of 22 patients,” the authors added.
Amputation-free survival, the primary safety and efficacy endpoint of the meta-analysis, was shown to increase by about 50% with PCB use compared to conventional balloon angioplasty (13.7% vs. 9.4% crude risk of death or limb loss, hazard ratio, 1.52; P=.008).
TLR, a secondary endpoint, was significantly reduced in patients treated with PCBs (11.8% vs. 25.6% for controls, risk ratio, 0.53; P=.004).
Katsanos et al published their newest meta-analysis on January 15th in the Journal of Vascular Interventional Radiology.1 Their findings come just a year after another study by the same group showed a significant increase in all-cause death at 2 years with paclitaxel-coated balloons and stents (compared to controls) in the femoral and/or popliteal arteries.2 The magnitude of this excess in mortality was increased at 5 years with the use of PCBs and paclitaxel-coated stents.
The earlier systematic review and meta-analysis2 pooled data from 28 randomized trials with 4663 patients treated with PCBs and paclitaxel-eluting stents. The authors suggested that many of the paclitaxel-eluting devices are different than the paclitaxel infusions used to treat cancer. Crystalline forms of paclitaxel are utilized in many of these devices; this formulation has a longer half-life and they hypothesize it may therefore be associated with more long-term complications.
The 2018 meta-analysis was a hot topic3 at ISET 2019 and beyond4, and led to a recommendation from the U.S. Food and Drug Administration5 that options other than PCBs and paclitaxel-eluting stents might “provide a more favorable benefit-risk profile based on currently available information.” They continue to monitor the situation and are working with manufacturers on labeling updates for paclitaxel-coated devices.
A subsequent study published shortly after ISET 2019 that reviewed Medicare and Medicaid claims data showed no evidence of increased all-cause mortality for patients who underwent femoropopliteal artery revascularization with paclitaxel-coated devices.6
Drug-coated balloons (DCBs) have been enthusiastically embraced as a means to decrease restenosis rates and the need for repeat intervention, but the clinical data on their use in the treatment of infrapopliteal disease has been decidedly mixed, with potential safety risks being raised as early as 2014 in the IN.PACT DEEP trial.7
New Meta-Analysis Moves Discussion Below the Knee
The researchers conducted a systematic review of the literature through September 2019, identifying 8 randomized controlled trials that compared PCBs with conventional balloon angioplasty for the treatment of CLI. Eight trials including 1420 patients, 97% of whom had CLI, were chosen for inclusion in the meta-analysis.
The trials tested any type of paclitaxel-coated balloon catheter. Two studies investigated a 3.5 μg/mm2 paclitaxel balloon surface density, 5 studies investigated a 3.0 μg/mm2 paclitaxel balloon surface density, and 1 study used a low-dose 2.0-μg/mm2 paclitaxel balloon surface density.
Interestingly, the harm signal appeared evident when examining the higher dose devices (3.0-3.5 μg/mm2), but attenuated below significance in the one study that used the 2.0 μg/mm2 device.
Five of 8 trials were multicenter in design and 3 of 8 followed patients for only 6 months; the remaining 5 trials continued follow-up to 1 year.
Through 1 year, there were 74 deaths and 40 major amputations among 835 patients in the paclitaxel arms, compared to 39 deaths and 17 major amputations among 585 patients in the uncoated balloon arms.
While the freedom from major amputation or death was lower with PCBs, with a pooled hazard ratio of 1.52, this composite signal of harm was driven by nonsignificant individual increases in both all-cause death (odds ratio, 1.39; P=.10) and major amputation (OR, 1.63; P=.09).
“…there was evidence of small study effects when analyzing deaths and amputations individually, which may imply the presence of publication bias,” wrote Katsanos et al.
Looked at individually, only one of the trials (SINGA-PACLI) included in the meta-analysis showed a significant difference in AFS between groups. That same study also showed a significant increase in major amputations with PCBs.
None of the 8 trials included in the meta-analysis — including IN.PACT DEEP with a hazard ratio of 1.73 and confidence intervals that just missed being statistically significant — were significant for a difference between PCBs and conventional angioplasty for the endpoint of all-cause death. For the combined AFS endpoint, the number needed to harm was estimated to be 22 patients.
No significant heterogeneity between studies was detected and no evidence of publication bias (P=.19). However, the authors did note that two studies, PICCOLO and EUROCANAL, both of which investigated PCBs in the infrapopliteal arteries, have never been released to the public.
“Actual causes for the detrimental clinical outcome remain largely unknown, but downstream and systemic paclitaxel embolization is a plausible mechanism,” wrote Katsanos and colleagues. “Further adequately powered multicenter studies with longer-term follow-up are urgently warranted.”
The authors noted several limitations of the current analysis: individual patient data were not available so only a summary trial-level analysis was possible; all studies were either open-label or single-blind with no systematic blinding of operators during application of the devices; and follow-up beyond one year was not available. As well, the actual causes of death and precise clinical indications to perform a major amputation were not reported.
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• Sahil A. Parikh, MD
• Thomas Zeller, MD, PhD
- Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Paraskevopoulos I, Karnabatidis D. Risk of death and amputation with use of paclitaxel-coated balloons in the infrapopliteal arteries for treatment of critical limb ischemia: a systematic review and meta-analysis of randomized controlled trials. J Vasc Interv Radiol. https://doi.org/10.1016/j.jvir.2019.11.015.
- Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: A systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2018 Dec 18; 7(24): e011245. doi: 10.1161/JAHA.118.011245.
- Paclitaxel Townhall: Is There Enough Concern to Alter Current Standards of Practice? ISET 2019. Available online at https://www.vasculardiseasemanagement.com/content/paclitaxel-townhall-how-will-you-continue-use-drug-eluting-technology. Accessed January 14, 2020.
- Veith FJ. Accepting the risk of treatment with drug-coated balloons. Vascular Disease Management 2019 June; 16(6). Available online at https://www.vasculardiseasemanagement.com/content/accepting-risk-treatment-drug-coated-balloons. Accessed January 14, 2020.
- August 7, 2019 Update: Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality. Letter to Healthcare Providers. U.S. Food and Drug Administration. Available online at https://www.fda.gov/medical-devices/letters-health-care-providers/august-7-2019-update-treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel. Accessed January 14, 2020.
- No evidence for increased mortality with drug-coated devices observed in Medicare database analysis. Vascular Disease Management. February 19, 2019. Available online at https://www.vasculardiseasemanagement.com/content/no-evidence-increased-mortality-drug-coated-devices-observed-medicare-database-analysis. Accessed January 14, 2020.
- Zeller T, Baumgartner I, Scheinert D, et al; IN.PACT DEEP Trial Investigators. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol. 2014 Oct 14; 64(15): 1568-1576. doi: 10.1016/j.jacc.2014.06.1198.