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Systematic Meta-analysis—A Scientific Gold Standard for All Therapies?

Thomas Zeller, MD

From the Department of Angiology, Clinic for Cardiology and Angiology II, University Heart Center Freiburg-Bad Krozingen, Bad Krozingen, Germany.

Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Zeller reports institutional grants for research, clinical trial, or drug studies received from Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Gore, Medtronic, Philips, Terumo, TriReme, Shockwave, Med Alliance, Intact Vascular, B. Braun, CSI, Boston Scientific, University of Jena, Pluristem, PQ Bypass, Surmodics, Alative Solutions, and Reflow Medical; consulting fees from Boston Scientific, CSI, Gore, Medtronic, Veryan, Philips-Intact Vascular, Shockwave, Bayer, Vesper Medical, and VentureMed; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott Vascular, BIBA Medical, Biotronik, Boston Scientific, Cook Medical, Gore, Medtronic, Philips-Spectranetics, Shockwave, and Veryan.

Address for correspondence: Prof Thomas Zeller, MD, Clinic for Cardiology and Angiology II, University Heart Center Freiburg—Bad Krozingen, Südring 15, 79189 Bad Krozingen, Germany. Email:

In contrast to a meta-analysis by Katsanos et al,1 the meta-analysis by Al Halabi et al2 in this issue the Journal of Critical Limb Ischemia examined paclitaxel-coated drug-coated balloon (DCB) angioplasty in infrapopliteal artery lesions and found significant benefits for the use of DCB regarding freedom from target-lesion revascularization (TLR), late lumen loss, and complete wound healing, and no difference in all-cause mortality, major amputation, and amputation-free survival.

However, we should be asking if meta-analyses of randomized controlled trials (RCTs) should be considered an appropriate method to evaluate the efficacy and safety of DCB angioplasty. RCTs are considered to be the highest scientific evidence (level 1a) when evaluating a therapy. The rationale for conducting a systematic review and meta-analysis is to overcome study cohort size limitations of individual studies by pooling data in an attempt to identify even small differences in effectiveness and/or safety of a new therapy compared with an established standard therapy. If a meta-analysis results in an effectiveness benefit, then a class effect is considered. Safety analysis of a drug-releasing device must include the safety of the device application and the drug delivered.  However, drug safety analysis must include potential additional exposure of the same drug during follow-up. How do these assumptions apply to the present meta-analysis?

Efficacy. What is the value of pooling data for identifying a potential class effect if there is obviously none? The IN.PACT Amphirion DCB (Medtronic) was voluntarily withdrawn from the market when the 1-year analysis of the IN.PACT Deep study missed its 1-year efficacy goal.3 However, this DCB type was used in 3 of 10 studies included in the present meta-analysis, including the largest of the included trials.4-6 A second DCB brand, the Passeo-18 Lux (Biotronik) was used in 2 of the studies, again without proof of efficacy.7 Finally, the Lutonix 14 DCB (Bard) tested in the second-largest RCT was not approved by the United States Food and Drug Administration, again due to a lack of efficacy.8 Thus, only 3 studies remain that showed superior efficacy over plain old balloon angioplasty. As such, the conclusion from the meta-analysis that “DCB use in infrapopliteal arteries is superior to PTA in improving clinical outcomes, angiographic results, and …” is misleading in the sense of suggesting a class effect for DCB efficacy in infrapopliteal interventions. The coating technology of DCBs designed for below-the-knee (BTK) interventions seems to be even more  important compared with those designed for treating femoropopliteal lesions. For BTK interventions, each individual balloon brand has to show technical superiority over a control device, which  is usually the plain, uncoated balloon in terms of either reducing late lumen loss and/or TLR rate, or increasing vessel patency. Without a technical benefit, clinical benefits can hardly be expected.

Safety. None of the published meta-analyses had access to individual patient data regarding total paclitaxel dose exposure during follow-up. Therefore, drug safety is only reliably assessed for the periprocedural period, and it is obvious that no acute systemic paclitaxel toxicity exists following DCB angioplasty of infrapopliteal arteries. However, the 2 major safety endpoints of the meta- analysis are all-cause mortality and major amputation. As for both endpoints, a potential side effect of the paclitaxel coating is that it is essential to calculate the life-time total paclitaxel dose exposed to each individual patient. This includes not only those patients who were initially treated with a paclitaxel-coated balloon, but also those whose index therapy was uncoated balloon angioplasty and then received paclitaxel-coated device therapy during follow-up. In a single-center study from Bad Krozingen, comprising 576 patients with BTK interventions, including 269 patients treated with uncoated devices without crossover to a paclitaxel-coated device during follow-up and 307 patients with DCB angioplasty, more than half of the patients treated with DCB underwent at least 1 additional intervention with a paclitaxel-coated device during a mean follow-up of 46 ± 33 months.9 The cumulative total paclitaxel dose was about 2.5 times higher than the index paclitaxel dose, without a negative impact on all-cause mortality. As the meta-analysis included only information about the paclitaxel dose during the index intervention, the second  conclusion that “DCB use in infrapopliteal arteries is…, with no increase in all-cause mortality or major amputations” must also be interpreted with caution. In conclusion, considering systematic review and meta-analysis of RCTs as the scientific gold standard only holds true if the analysis applies to an appropriate patient population with access to complete endpoint-related data. Nevertheless, in opposition to the previous meta-analysis published by Katsanos et al, the current meta-analysis could not confirm a decrease in the combined endpoint of amputation-free survival.1


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. 2020;31(2):202-212. Epub 2020 Jan 15. doi: 10.1016/j.jvir.2019.11.015
2. Al Halabi S, Templeton E, Heaney C, et al. Drug-coated versus uncoated percutaneous transluminal angioplasty balloons for the treatment of infrapopliteal peripheral artery disease: a systematic review and meta-analysis of randomized controlled trials. J Crit Limb Ischem 2022;2(1):E11-E16. Epub 2021 Dec 22.
3. Zeller T, Baumgartner I, Scheinert D, et al. 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;64(15):1568-1576. doi: 10.1016/j.jacc.2014.06.1198
4. Zeller T, Micari A, Scheinert D, et al. The IN.PACT DEEP clinical drug-coated balloon trial: 5-year outcomes. JACC Cardiovasc Interv. 2020;13(4):431-443. doi: 10.1016/j.jcin.2019.10.059
5. Liistro F, Porto I, Angioli P, et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation. 2013;128(6):615-621. doi: 10.1161/CIRCULATIONAHA.113.001811
6. Fanelli F, Cannavale A, Corona M, Lucatelli P, Wlderk A, Salvatori FM. The “DEBEL-LUM”—lower limb multilevel treatment with drug eluting balloon—randomized trial: 1-year results. J Cardiovasc Surg (Torino). 2014;55(2):207-216.
7. Zeller T, Beschorner U, Pilger E, et al. Paclitaxel-coated balloon in infrapopliteal arteries: 12-month results from the BIOLUX P-II randomized trial (Biotronik’s first in man study of the Passeo-18 Lux drug releasing PTA balloon catheter vs the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries). JACC Cardiovasc Interv. 2015;8(12):1614-1622. doi: 10.1016/j.jcin.2015.07.011
8. FDA Panel Meeting, February 17 2021. Accessed March 4, 2022.
9. Böhme T, Beschorner U, Noory E, et al. Evaluation of mortality following paclitaxel drug-coated balloon angioplasty of infrapopliteal lesions in real world. Texas Heart J. 2022 (under revision).