Commentary Regarding Katsanos et al`s Meta-Analysis: What Do We Learn From These New Data?

In a new meta-analysis on the clinical outcome of patients suffering from below-the-knee (BTK) arterial disease and mainly critical limb threatening ischemia (CLTI) published this week in JVIR¹, Katsanos et al again raise concerns regarding the safety of paclitaxel-coated drug-eluting balloons (DCB).

This meta-analysis includes 8 randomized (controlled?) trials with 1420 patients (835 DCB, 585 POBA) with a clinical follow-up ranging from 6 months to one year. In 5 of the 8 studies, data from congress reports are included in the meta-analysis. The primary endpoint of the study is amputation-free survival (AFS), and secondary endpoints are all-cause death, major amputation, and target lesion revascularization (TLR) rates. AFS was significantly worse for the DCB group [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.12 – 2.07, P=.008], whereas all-cause mortality and amputation rates did not show a statistically significant difference. The TLR rate was significantly lower after DCB treatment (HR 0.53, 95%CI 0.35 – 0.81, P=.004). Again, same as for DCB application in femoro-popliteal arteries, the authors postulate a dose-dependent increase of risk of mortality and amputation rate with “high dose” DCB devices. 

What do we learn from these new data? Katsanos et al conclude “there appears to be increased risk of death or major limb loss during the first year when PCBs are applied in the infrapopliteal arteries for CLI treatment. Actual causes for this detrimental clinical outcome remain largely unknown, but downstream and systemic paclitaxel embolization is a plausible mechanism.” First of all, the conclusion is wrong — the study does not show an increased risk “of death or major limb loss”: the all-cause death rate does not significantly differ between the study groups (HR 1.39, 95%CI 0.94 – 2.07) nor does major amputation rate (HR 1.63, 95% CI 0.92 – 2.90). It is the combination of both endpoints, which is AFS, that is favoring the POBA strategy.

Are the findings real? The review includes study data derived from study-level data published or presented at recent congresses. Three out of 8 studies are single-center studies without independent clinical events committee adjudication of the safety events, 3 out of 8 studies analyzed are not yet published congress reports, and the data may be subject to change during the publication process.

The “trend to an increased all-cause mortality risk” following DCB exposure in this study is not in line with the finding of the same study group for the treatment of femoro-popliteal disease with DCB.² In the former study, all-cause mortality rate was identical at 1-year follow-up, whereas in the present study, mortality rate was already higher after a short follow-up of only 6 to 12 months. If paclitaxel exposure during DCB treatment should result in a chronic systemic toxic effect as claimed by Katsanos et al, it should result in a uniform time to harm from exposure in particular, considering that the paclitaxel doses applied during treatment of femoro-popliteal disease are much higher as compared to BTK disease. In addition, assuming a toxic drug effect, a dose dependency of the mortality endpoint is crucial. The study found a lower mortality rate for “low dose” DCB defined as 2.0 µg/mm² compared to “high dose” DCB (3.0 to 3.5 µg/mm²). However, only 1 out of 8 studies used a “low dose” device and for this particular study, only 6-month follow-up data are published.

The trend towards a non-significant higher major amputation rate following DCB treatment in short-time follow-up must be interpreted with caution. Only one study (SINGA-PACLI) reported a significantly increased amputation rate at one year. The major amputation rate is a study endpoint with high potential for bias, due to the lack of uniform post-procedure wound care guidelines. In addition, study cohorts included into the meta-analysis are hard to compare, particularly regarding disease severity in terms of the presence of wounds or ulcers, which ranges from 56.1% in Lutonix BTK — the only “low-dose” DCB study — to 96.5% in DEBATE-BTK and SINGA-PACLI. In addition, the patients included in DEBATE-BTK were 100% diabetics. The combination of diabetes and wounds characterizes a high-risk patient population for amputation. Nevertheless, DEBATE-BTK resulted in the lowest odds ratio for major amputation despite the use of a “high-dose” DCB (3.5 µg/mm²), which disproves the authors’ suggestion of dose-dependent local tissue toxicity. 

In summary, the current meta-analysis raises concerns regarding the short term safety of paclitaxel-coated DCB treatment of BTK disease in a CLTI study population resulting in a significantly reduced AFS rate after a follow-up of 6 to 12 months. The study is characterized by major limitations, but the safety signal deserves a higher quality data workup, including patient-level data analysis and a longer-term follow-up of at least 3 years, considering the high general mortality rate of a CLTI study population. Interestingly, in the IN.PACT DEEP trial, the only study with a published 5-year follow-up to date³, the composite endpoint consisting of all-cause death, major amputation, and CD-TLR was identical for both study cohorts (DCB 59.8% vs. POBA 57.5%, P=.309) as well as the all-cause mortality rate (DCB 39.4% vs. POBA 44.9%, P=.727).  n

Disclosure: Dr Zeller reports honoraria received from: Abbott Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Philips-Spectranetics, Shockwave, BIBA Medical. He has consulted for: Boston Scientific Corp., CSI, Gore & Associates, Medtronic, Veryan, Intact Vascular, Shockwave, Bayer, Vesper Medical Dr Zeller also reports the following research, clinical trial, or drug study funds received from (institution): Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Gore & Associates, Medtronic, Philips, Terumo, TriReme, Shockwave, Med Alliance, Intact Vascular, B. Braun; CSI, Boston Scientific, University of Jena. Common stock: QT Medical.

Address for correspondence: Professor Thomas Zeller, MD, PhD, can be contacted at thomas.zeller@universitaets-herzzentrum.de.

References

1. 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.

2. 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.

3. Zeller T, Micari A, Scheinert D, et al. The IN.PACT DEEP clinical drug-coated balloon trial 5-year outcomes. JACC Cardiovasc Interv 2019 accepted. [In press].