Hotly-contested meta-analysis suggests a higher risk of death or amputation at one year when paclitaxel-coated balloons are used in infrapopliteal arteries

Credit line ID 116817571 © Tridsanu Thopet
Credit line ID 116817571 © Tridsanu Thopet

A new meta-analysis, just published in the Journal of Vascular and Interventional Radiology (JVIR), suggests significantly worse amputation-free survival at one year with the use of paclitaxel-coated balloons in arteries below the knee in the treatment of chronic limb-threatening ischaemia (CLTI). However, some experts advise cautious interpretation of results and question whether these data will impact practice. The new systematic review and study-level meta-analysis of eight randomised controlled trials was conducted by Konstantinos Katsanos (School of Medicine, University of Patras, Patras, Greece) and colleagues.

Several physician thought-leaders believe that the conclusions are not yet definitive, with multiple vascular surgeons and interventionalists cautioning how these data should be interpreted. Most emphasised the challenge of teasing out scientifically meaningful information from a patient cohort that suffered from CLTI, which is associated with “mortality, amputation, and impaired quality of life”. They also point to the inclusion of unpublished data (which has therefore not gone through the peer-reviewed process); the inclusion of summary-level data; the inclusion of the IN.PACT DEEP data (which used a device that has long since been withdrawn from the market); and the study’s short-term follow-up period.

As reported in JVIR, the eight randomised controlled trials included in this most recent summary-level analysis included 1,420 patients, of which 1,380 (97.1%) had CLTI. The primary safety and efficacy endpoint was amputation-free survival, defined as freedom from all-cause death and major amputation (above the ankle). At one year, there was a 13.7% crude risk of death or limb loss among the 835 patients who had received treatment with paclitaxel-coated balloon—74 deaths and 40 major amputations. In comparison, the crude risk of death or limb loss in the cohort treated with an uncoated balloon was 9.4%—39 deaths and 17 major amputations. For the primary amputation-free survival endpoint, the number needed to harm was estimated to be 22 patients (95% confidence interval [CI] 11–94). The authors claim there was consistent evidence from the randomised studies that freedom from major amputation or death was significantly lower in cases with paclitaxel-coated balloons with a pooled hazard ratio (HR) of 1.52 (95% CI 1.12–2.07; p=0.008).

However, Katsanos et al also report consistent evidence that paclitaxel reduces the need for target lesion revascularisation in below-the-knee arteries by approximately 40%. Target lesion revascularisation constituted the secondary efficacy endpoint. The crude risk of target lesion revascularisation was 11.8% (103 revascularisation events among 875 cases) versus 25.6% (159 events among 620 control patients) for patients treated with a paclitaxel-coated balloon and an uncoated balloon, respectively. The calculated pooled risk ratio was 0.53 (95% CI 0.35–0.81; p=0.004), with a corresponding number needed to treat of eight patients (95% CI 4–25).

The study authors claim there is a dose–response relationship between paclitaxel and amputation-free survival. They compared outcomes with low and high doses of paclitaxel, and found significantly more deaths or amputations (lower amputation-free survival) in cases with high-dose devices, defined as 3–3.5µg/mm2 (HR 1.62; 95% CI 1.16–2.27; p=0.005). In comparison, amputation-free survival was higher (fewer deaths or fewer major amputations) when a low-dose device (2µg/mm2) was used (HR 1.06; 95% CI 0.48–2.34). This low-dose was found to be safe and effective, the authors report.

The authors of the present study say they performed a “comprehensive literature review” due to the “major concerns about systemic safety of paclitaxel” prolific in the endovascular community today as a result of their earlier meta-analysis published in the Journal of the American Heart Association (JAHA) in 2018. This concluded that there was an increased association of mortality beyond two years through five years of follow-up when paclitaxel-coated balloons and paclitaxel-eluting stents were used in the femoropopliteal arteries.

Concerns of the medical community: The vascular surgeon perspective

Kim Hodgson, president of the Society for Vascular Surgery
Kim Hodgson

Kim Hodgson, president of the Society for Vascular Surgery (SVS); Southern Illinois University School of Medicine, Springfield, USA

“While this analysis of the efficacy and mortality of paclitaxel use in the infrapopliteal CLTI population has similar methodological limitations to the first Katsanos publication of paclitaxel used to treat claudication, it also reaches the similar concerning conclusion that paclitaxel use in peripheral vascular disease is associated with increased mortality. But this time the authors use the most relevant of clinical endpoints for this population, amputation-free-survival, to evaluate for the ultimate goal of an intact living patient. While it took use of this composite endpoint to achieve statistical significance, it is alarming that both mortality and amputation came very close to independently reaching statistical significance (p=0.1; p=0.09, respectively), and I suspect that with a larger sample size one or both they may have. If further evidence confirms either that paclitaxel does not decrease the rate of amputation but does increase the mortality, then the prospects for its continued use appear bleak. The possible ray of sunshine in this cloud is the observation that the lowest dose paclitaxel device analysed (Lutonix, BD) appeared to be free of increased mortality yet still effective, perhaps indicating that the dosing sweet-spot has yet to be found while acknowledging that we have no accurate way of measuring actual paclitaxel tissue delivery or systemic release.  The complicated nature of paclitaxel delivery and its pharmacology, however, portend that this will remain a complicated mystery to unravel.

“There has been a significant shift towards the use of paclitaxel delivering devices in treating peripheral vascular disease since their introduction several years back. Given this and the ever growing population of peripheral vascular disease patients being treated, it is critical that physicians know the full risk:benefit profile of the therapies they employ and always put the patient’s outcome first. The methodological limitations of this pooled analysis are divulged by Katsanos and are similar to those of his previous publication on the use of paclitaxel in the claudication population.  Nonetheless, his prior report called attention to a signal that was, in fact, subsequently confirmed, though still not understood, so the findings of this analysis are highly relevant and need further analysis.

“When considering a risk like mortality, erring on the side of caution only makes sense, especially considering the multitude of other revascularisation options available to most patients, the irreversibility of death, and the risk of litigation. This is especially true when the effectiveness of the therapy itself is in question, as this analysis has suggested. Until we have greater clarity on the safety and efficacy of paclitaxel devices, I believe that most will opt to use them very selectively in the small subset of patients at high risk for restenosis and no other reasonable revascularisation options.”

Ramon Varcoe, Prince of Wales Hospital and University of New South Wales, Sydney, Australia
Ramon Varcoe

Ramon Varcoe, Prince of Wales Hospital and University of New South Wales, Sydney, Australia

“My first reaction was that it was good to see a group looking to define the risks of paclitaxel devices in the CLTI population. The CLTI group is very different to the claudicants evaluated in the previous meta-analysis and warrants specific attention.

“My reaction to the results was mixed. The authors showed no difference in all-cause mortality or major amputation rates but when they combined the two as the endpoint amputation-free survival, they appeared to find a difference between drug-coated balloons and percutaneous transluminal angioplasty, with better amputation-free survival in the control group. The other positive finding was that they showed a 47% reduction in reinterventions, underlining the well-established effectiveness of these devices.

“It must be said from the outset that—with limited numbers and such short-term follow-up—care must be taken not to overreach in our conclusions. Moreover, taking a deeper dive into the meta-analysis revealed several methodological questions and important validity concerns.

“For example, why were only drug-coated balloons evaluated and not drug-eluting stents? This differed from the methodology of the previous meta-analysis and meant excluding the PADI trial, which has published five-year follow-up. This is the very group identified in the previous meta-analysis as having the most pronounced safety signal. Second, why was amputation-free survival determined to be the primary endpoint, when all-cause mortality was used in the previous meta-analysis? Why was no protocol published on the PROSPERO database to assure the reader that the endpoint was determined a priori, not after the analysis? Third, why were only below-the-knee studies included when the authors speculate it is the particulate embolisation of the drug that provides an explanation for the safety signal? Particulate embolisation is known to occur when CLTI patients are treated for above- and below-the-knee disease. However, ultimately these are questions for the authors, which may have a reasonable explanation.

“My major concern is the inclusion of unpublished data. This was the case in three of the eight studies pooled. We must take great care in including data that has not been peer reviewed. It is common that event rates change between presentation and final publication, which may alter the findings of a meta-analysis and its conclusions. This is particularly true for low-frequency endpoints such as amputation-free survival at six to 12 months. It is also very difficult for the reviewers to grade the quality of evidence from a short congress presentation, as opposed to a peer-reviewed manuscript. However, including unpublished data is not unheard of, particularly when there are few published studies in the literature. What concerns me most is the glaring omission of the most significant study of drug-coated balloon use in below-the-knee arteries of CLTI patients. The five-year results of the IN.PACT DEEP study were presented by Thomas Zeller at the AMP symposium last year (14–17 August, Chicago, USA). Like the other three studies, it was unpublished in September 2019 when the systematic review was conducted. However, if you include some unpublished data you must include all.

“IN.PACT DEEP was a rigorously conducted trial which fulfilled all of the inclusion criteria for the meta-analysis, as evidenced by inclusion of its earlier 12-month results. In that study, amputation-free survival was numerically better in the drug-coated balloon group (drug-coated balloon 135/239 [56.5%] vs percutaneous transluminal angioplasty 65/119 [54.6%]). The inclusion of such a study is important for two reasons. It provides long-term follow-up, which was linked to mortality in the original meta-analysis in claudicants and it had a high number of events (death and amputation). Statistically, meta-analysis gives additional weight to large studies with high event rates because observed differences are less likely to be due to chance. It is my view that if those contemporary results had been included in this meta-analysis, the conclusions regarding amputation-free survival and safety would have been very different. Given the reintervention reducing benefit of drug-coated balloons, the authors have demonstrated we must get this right. A serious omission such as this must be corrected if we are to determine the truth—our very patients’ lives depend on it.

“These results are under a cloud due to methodological questions and the omission of the most important study. This should not impact anyone’s practice until those issues have been addressed.”

Michael Conte

Michael Conte, Heart and Vascular Center, University of California, San Francisco, San Francisco, USA

“I do not think this is really a big surprise, as the results from IN.PACT DEEP regarding a higher observed rate of major amputation in the paclitaxel-coated balloon arm have been known, and the only other reasonably large study (Lutonix BTK) has yet to report one-year data. The other six trials are modest in size and the number of events is small. So the pooled data is dominated by the two larger trials, only one of which has reported one-year data with these effects known. There are and have been concerns about the adverse effects of paclitaxel embolisation in CLTI patients and this publication keeps the issue on the front-burner but does not resolve it much further.

“CLTI is a major global health problem and current treatments have significant limitations, contributing to high morbidity and mortality rates in these patients. Interventions for infra-popliteal arteries, in particular, have high rates of failure and thus there is considerable unmet need for more effective approaches. Thus the interest in various methods to improve the results of angioplasty, such as drug-elution, remains high.

“The limitations of this study relate to both the analysis itself and, more importantly, the state of the field it reflects. The meta-analysis involves pooled data and is not patient-level. Thus it is not possible to evaluate confounders (e.g. unbalanced comorbidities or clinical severity) that may be driving the outcomes. The actual event rates in these trials are lower than expected across the board, e.g. overall major amputation rate of 4% suggesting that the degree of limb threat at presentation may have been modest. The two larger trials employed a 2:1 randomisation ratio, leading to a significantly larger population with PCB exposure than controls. As stated above, the results are dominated by the two larger studies, and these studies have only reported short to mid-term outcomes. This is particularly relevant for the death outcome. CLTI itself has a broad clinical spectrum and the need for improved staging systems (for example, the Society for Vascular Surgery Wifi classification system) is evident to allow for better trial designs and balanced randomisation by limb severity. Finally, one has to ask—where are the five-year data from IN.PACT DEEP and where are the one-year data from Lutonix BTK? The vascular community deserves timely, complete, and honest reporting from the trials.

“The conclusions are cautiously stated by the authors and reflect the current data available. But the quality and quantity of data available in this space remains seriously lacking.

“No [I do not think the paper will change practice] because in the USA there are no currently approved paclitaxel-coated balloons for the infrapopliteal arteries at this time. It will be interesting to see if the final results of Lutonix BTK are reported and whether they allow for regulatory approval by the FDA. Until then I believe it is reasonable to continue to conduct appropriately monitored, well-designed RCTs to evaluate the safety and efficacy of drug-eluting devices for CLTI given the significant unmet need.”

Concerns of the medical community: The interventional radiologist perspective

Laura Findeiss, president of the Society of Interventional Radiology (SIR); Emory University School of Medicine, Atlanta, USA
Laura Findeiss

Laura Findeiss, president of the Society of Interventional Radiology (SIR); Emory University School of Medicine, Atlanta, USA

“The paper published today by Konstantinos Katsanos and colleagues raises important questions about the treatment of patients with CLTI, and is an important contribution to the medical literature. As with any meta-analysis, validation of the findings will require further dedicated investigation. In particular, the lack of patient-level data and the inclusion of unpublished data sets in this analysis may weaken the strength of the conclusions.

“Patients with CLTI are vulnerable and have few care options. It is important to know what treatments will best enhance their life expectancy and quality of life. The Society of Interventional Radiology will continue to work with the [US] Food and Drug Administration to support its work in developing practice guidance on the use of paclitaxel-coated balloons in the infrapopliteal arteries for CLTI treatment as we look to build rigorous scientific evidence for available treatments.”

Robert Morgan, past president of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE); St George’s Hospital, London, UK
Robert Morgan

Robert Morgan, past president of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE); St George’s Hospital, London, UK

“It is an interesting publication that unfortunately adds little to the overall lack of conclusive evidence supporting the use of paclitaxel-coated devices in the infrapopliteal circulation in patients with CLTI.

“I am concerned that flaws in systematic reviews highlighted in universal comments on the authors’ previous meta-analysis in JAHA may also have contributed to the negative results for paclitaxel-coated balloons in this systematic review. No doubt this paper will excite many comments and publications on this topic in the next 12 months.

“The topic is a very important one considering the ongoing controversy of paclitaxel-coated devices in the femoropopliteal circulation. The subject is muddied by the potential adverse effects of different excipients and the lack of individual patient safety data. I do not think that this contributes significantly to the ongoing controversy regarding any potential link between paclitaxel-coated balloons and mortality. However, the authors’ conclusion that distal embolisation of paclitaxel and/or excipient may adversely affect amputation-free survival is reasonable. Finally, the inclusion of the IN.PACT DEEP data (using a withdrawn device) involving almost a third of the patients in this review, with its known negative influence on mortality and amputation-free survival, is likely to have adversely contributed to the overall negative results on amputation-free survival in this publication.

“In common with most vascular practitioners in the UK, I do not use paclitaxel-eluting devices below the knee in patients with CLTI. This is partly due to the Medicines and Healthcare products Regulatory Agency (MHRA) statement on paclitaxel devices in 2019, and partly due to a perception of lack of efficacy of these devices in CLTI. In view of the above, these data will not impact my current vascular practice.”

Michael Dake, president-elect of the Society of Interventional Radiology (SIR); University of Arizona Health Sciences, Tucson, USA
Michael Dake

Michael Dake, president-elect of the Society of Interventional Radiology (SIR); University of Arizona Health Sciences, Tucson, USA

“Aside from The Godfather Part II, sequels are rarely as compelling as the original version, often with an impact that is a mere ripple of the force produced by the initial statement. Predictably, I suspect this will be the case for the current report, although its contribution to the medical literature will be of interest to many stakeholders in the field of vascular disease.

“The results of this meta-analysis of randomised controlled trials focused on patients with CLTI are more difficult to interpret than the earlier femoropopliteal publication. The medical complexity of the underlying disease and the vulnerability of CLTI patients contribute to a greater heterogeneity in the population studied. Consequently, added caution must be exercised when attempting to make conclusions from this meta-analysis.

“In terms of the methodology used, the current study shares some of the frequently noted limitations of the original femoropopliteal meta-analysis. The lack of patient-level data available to the authors from the randomised studies included in the meta-analysis restricts evaluation of the total dose of paclitaxel used in individual patients and any correlation with mortality. In addition, the relatively small number of patients analysed and [the] short follow-up (46% of the patients had only six-month follow-up) make any conclusions problematic. Unlike the first meta-analysis, however, an additional limitation is noted. The current report of pooled trials includes unpublished data. Results from three of the eight trials used in the analysis have not been published. This represents one-quarter of the patients included.

“Nevertheless, the paper raises interesting points about the effect of drug-coated balloon treatment for patients with CLTI, and questions the possible association of downstream drug embolisation and amputation in patients with compromised distal arterial circulation. In addition, it echoes the call after the earlier femoropopliteal publication for more data and an urgent need for adequately-powered multicentre studies with longer follow-up. Its effect on clinical practice for management of CLTI patients with limited treatment options is questionable. Most likely, future substantiation using larger, well-controlled trials will be required before changing strategies for the application of drug-coated balloons in treating CLTI.”

John Kaufman, Oregon Health & Science University, Portland, USA
John Kaufman

John Kaufman, Oregon Health & Science University, Portland, USA

“Concerns about drug-eluting balloons in the tibial arteries have been around since the DEBATE-BTK and IN.PACT DEEP trials, so while not as disruptive as the prior study from this group, this new meta-analysis certainly adds more grist to the paclitaxel mill. Some of the same limitations of the previous study apply here: the absence of patient-level data, and differences in the technologies between trials. Most patients in this meta-analysis had CLTI, a more challenging population than the patients with claudication due to the femoropopliteal artery that dominated the previous study. Other differences are that only balloon-based devices were studied, there are a paucity of data on inflow and target lesion revascularisation procedures, and the number of patients analysed is smaller. Of note, data from several of the included trials are only available as conference presentations online, rather than peer-reviewed publications. However, most important is that the follow-up is far shorter than in the previous meta-analysis—between six months and 12 months. Is it possible that over time we will see these amputation and mortality rates stabilise or even equalise? Will extended follow-up of patients treated with new devices bend the curves in the right direction? With this new analysis we are left in the same place as before; paclitaxel devices have better lesion-based outcomes, but there may be trade-offs. We need to be really thoughtful as we learn how and when to best use them, especially in the tibial arteries.”

Jim Reekers, CVIR Endovascular editor-in-chief; Academic Medical Center, Amsterdam, The Netherlands
Jim Reekers

Jim Reekers, CVIR Endovascular editor-in-chief; Academic Medical Center, Amsterdam, The Netherlands

“Reading the methodologically-excellent paper by Katsanos et al, their conclusions do not come as a surprise. The so called “low flow” phenomenon after drug-coated balloon use was recognised in coronary arteries four years ago. Also, the observation of “slow flow” directly after peripheral drug-coated balloon [use] has been discussed by others in the corridors of several meetings. In our department, drug-coated balloons are used very scarcely (four a year for recurrent early superficial femoral artery restenosis only), but we have already seen two patients with instant reduction of foot perfusion after drug-coated balloon use in the superficial femoral arteries. This acute reduction in flow was documented with perfusion angiography. These were both patients with intermittent claudication where no clinical consequences were seen, probably due to the sufficient reserve capacity of the microcirculation perfusion. However, in serious CLTI, this embolisation could have devastating consequences for the outcome. This also proves that, at least partly, micro-particles loaded with paclitaxel are trapped in the microcirculation. A simple prospective trial using perfusion angiography after drug-coated balloon implantation would be enough to prove this micro-particle embolisation as cause for a reduction in amputation-free survival.

“In Katsanos et al’s paper, the hazard ratios are calculated for amputation-free survival as a primary clinical endpoint, and target lesions revascularisation is a secondary non-clinical endpoint. A secondary endpoint can sometimes be used for clinical decision-making if the primary endpoint of a study is borderline statistically not significant or equivalent. Mostly, a secondary endpoint is used to calculate the cost-efficacy of a treatment. The fact that the target lesion revascularisation is 50% better after drug-coated balloon use is, however, irrelevant if the primary clinical endpoint (amputation-free survival) shows that the hazard ratio for a lower amputation-free survival is 1.52 after the use of a drug-coated balloon. This strong primary clinical endpoint makes any drug-coated balloon treatment questionable.

“Combining the previously-documented data of a mortality increase with paclitaxel-coated devices after two and five years with this new findings of a lower amputation-free survival after drug-coated balloon use in CLTI patients should make us seriously re-think the concept of drug-coated balloons in CLTI as a (failed) treatment concept.”

Gunnar Tepe, Klinikum Rosenheim, Rosenheim, Germany
Gunnar Tepe

Gunnar Tepe, Klinikum Rosenheim, Rosenheim, Germany

“I have two immediate remarks:

  1. “It is very important to look into safety issues of devices in general. Therefore, all data have to be taken seriously.
  2. “Compared to the first publication from Katsanos et al, the statistical part is much more solid.

“Nevertheless, there are several major limitations of the recent publication:

  1. “In order to achieve a certain number of patients, the follow-up time was mixed—some studies follow the patients for six months, some trials have a 12-month follow-up.
  2. “Katsanos et al state that they did a meta-analysis based on eight studies. In fact, the meta-analysis is driven by two high-volume studies only. This is the Lutonix BTK study with a six month endpoint, and the IN.PACT DEEP study with a 12 month endpoint. The finding that amputation-free survival is decreased in patients who received paclitaxel-coated balloon angioplasty below-the-knee is driven by the IN.PACT DEEP study, which has high patient numbers. This is nothing new and has been published. Nevertheless, even the data available to Katsanos et al do not discuss that. For the IN.PACT DEEP study, we know from data presented at conferences that at five years, patients who received drug-coated balloons had a better amputation-free survival.
  3. “Dose issue: Katsanos et al state that a higher dose is followed by more amputations. This is a wrong statement. All below-the-knee drug-coated balloons are low-dose applications compared to what is given in the superficial femoral arteries. We know from several studies that patients with CLTI and drug-coated balloon treatment in the superficial femoral arteries do fine. There were fewer target lesion revascularisations, but no increase of amputations or deaths. It is totally misleading the Katsanos et al ignore this fact.
  4. “Another mistake is that Katsanos et al do not take into account that most likely almost all patients have received paclitaxel-coated balloons in their history—either in the same leg, in another location, or for target lesion revascularisation. It is not OK that he just states in the discussion that this is unknown.

“In summary: Katsanos et al unfortunately increase the uncertainty in the safety of drug-eluting technology. What does it end with? Fewer patients will get drug-coated balloons and more target lesion revascularisations and [consequently] more amputations may occur. Does it affect my clinical practice? No, for two reasons:

  1. “I think (also [in accordance with] what has been published within the last year) that paclitaxel-coated balloons are safe
  2. “In CLTI patients with below-the-knee treatment, the long-term patency is not as important as in claudicants patients. It is also feasible to proceed with plain balloon angioplasty. In the superficial femoral artery, my primary choice is drug-coated balloon treatment; in below-the-knee arteries it is plain balloon angioplasty.”

Concerns of the medical community: The interventional cardiologist perspective

Gary Ansel, OhioHealth Heart and Vascular Physicians, Columbus, USA
Gary Ansel

Gary Ansel, OhioHealth Heart and Vascular Physicians, Columbus, USA

“In my view, this manuscript may very well misinform the medical community and the patients we serve. It is important to note that the scientific community has been utilising higher level scientific analyses (i.e. patient-level data) to evaluate the role of paclitaxel in peripheral vascular procedures. The original question of whether paclitaxel has adverse outcomes in these procedures was a good one. However, there is a need to react scientifically to any potential investigator bias and ascertainment bias in the original data sets as well as the patient level data from the randomised trials and very large real-world data.

“First, patient care including safety and outcomes are foremost in my thoughts. However, this manuscript included data from non-peer reviewed studies presented at medical symposia as well as single-centre datasets and data published in lower-tiered journals. Both of these types of data, especially with the low total number of patients may be interesting, but do not have the level of accuracy to apply to a meta-analysis trying to make definitive patient safety claims. One of the cardinal sins for meta-analyses is to try and prove a point or to go in with an agenda.

“It is interesting that the authors chose to utilise certain data sets from the public sector, while at the same time leaving out others such as the many presentations of the longer-term follow-up of the INPACT DEEP study where the risk of amputation and survival actually reverse with uncoated balloon angioplasty demonstrating more risk. There have also been numerous presentations in the femoropopliteal bed with DCB (with an actual patient-level data meta-analysis) demonstrating a continuously decreasing relative risk as more complete follow-up data is obtained. These data have been submitted for publication and are under evaluation.

“The relevance of CLTI is important as typically there has been a “mantra” from the current authors that much larger public data sets that have been published without any safety signal has been due to the dilution by the increased risk of the critical limb population. The authors do not even address the fact that their first data sets evaluating the potential mortality signal appeared at a delayed time point of over a year, and here they seemingly find it at 6–12 months?  This publication serves no useful purpose, in my opinion.”

Thomas Zeller, Universitäts-Herzzentrum Freiburg, Bad Krozingen, Germany
Thomas Zeller

Thomas Zeller, Universitäts-Herzzentrum Freiburg, Bad Krozingen, Germany

“I was surprised about the inclusion of short-term outcomes in this study—the follow-up period ranges from six to 12 months. In a previous meta-analysis of the same study group regarding safety of paclitaxel-coated balloon use in femoropopliteal artery disease, absolutely no safety concern was evident at one-year follow-up. Now, in the present study, the authors raise a safety concern already within a couple of months after paclitaxel exposure that does not fit together with their assumption of an increased mortality risk as the consequence of a chronic paclitaxel toxicity due to disseminated multi-organ embolisation.

“The study data must be interpreted with caution due to several reasons. The limitations of the present meta-analysis are even more relevant as compared to the previous one related to femoropopliteal disease treatment. The overall study size of 1,420 patients is meaningful but still underpowered regarding the primary endpoint amputation-free survival considering the wide variation of the numbers found in the literature for the both individual endpoints: all-cause death and major amputation rate. In five of the eight studies, data from congress reports are included in the meta-analysis. The primary endpoint of the study is amputation-free survival. Secondary endpoints are all-cause death, major amputation, and target lesion revascularisation rates. Amputation-free survival was significantly worse for the drug-coated balloon group (HR 1.52, 95% CI 1.12–2.07, p=0.008), whereas all-cause mortality and amputation rates were not statistically significant different. The target lesion revascularisation rate was significantly lower after drug-coated balloon treatment (HR 0.53, 95% CI 0.35–0.81, p=0.004). Again, same as for drug-coated balloon application in femoropopliteal arteries, the authors postulate a dose-dependent increase of risk of mortality and amputation rate with “high-dose” drug-coated balloon devices.

“Katsanos et al conclude: “There appears to be an increased risk of death or major limb loss during the first year when paclitaxel-coated balloons are applied in the infrapopliteal arteries for CLTI treatment. Actual causes for this detrimental clinical outcome remain largely unknown, but downstream and systemic paclitaxel embolisation 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”: 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—amputation-free survival—that is favouring the percutaneous transluminal angioplasty strategy.

“Are the findings real? The review includes study data derived from study-level data published or presented on recent congresses. Three out of eight studies are single-centre studies without independent clinical events committee adjudication of the safety events, three out of eight studies analysed are not yet published congress reports and the data may be subject of change during the publication process.

“The “trend to an increased all-cause mortality risk” following drug-coated balloon exposure in this study is not in line with the finding of the same study group for the treatment of femoropopliteal disease with drug-coated balloon. In the former study, the all-cause mortality rate was identical at one-year follow-up, whereas in the present study mortality rate was already higher after a short-time follow-up of six to 12 months only. If paclitaxel exposure during drug-coated balloon 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 femoropopliteal disease is much higher as compared to below-the-knee 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” drug-coated balloon, defined as 2μg/mm2, compared to “high-dose” drug-coated balloon (3–3.5μg/mm2). However, only one out of eight studies used a “low-dose” device and for this particular study only six-month follow-up data are published.

“The trend towards a non-significant higher major amputation rate following drug-coated balloon treatment in short-time follow-up must be interpreted with caution. Only one study (SINGA-PACLI) reported a significantly increased one-year amputation rate at one year. 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 in the meta-analysis are hard to be comparable regarding disease severity, in particular regarding the presence of wounds or ulcers ranging from 56.1% in Lutonix BTK—the only “low-dose” drug-coated balloon study—to 96.5% in DEBATE-BTK and SINGA-PACLI. In addition, patients included DEBATE-BTK were in 100% diabetics. The combination of diabetes and wounds characterises 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 (3.5μg/mm2) that disproves the suggestion of the authors of dose-dependent local tissue toxicity.

“In summary, the current meta-analysis raises concerns regarding the short-term safety of paclitaxel-coated balloon treatment of below-the-knee disease in a CLTI study population resulting in a significantly reduced amputation-free survival rate after a follow-up of six to 12 months. Not going into statistical details, the study is characterised by major limitations but the safety signal deserves a higher quality data work-up including patient level data analysis and a longer-term follow-up of at least three years considering the high general mortality rate of a CLTI study population.

“These data will not impact practice because, as a result of the JAHA publication in 2018, drug-coated balloons are, in general, already used with caution. In addition, until the recent congress presentations of ACOART II (Guo et al, LINC 2019, Leipzig, Germany) and ACOART BTK (Liistro, VEITH 2019, New York, USA) no clear evidence existed regarding the technical efficacy of drug-coated balloons in below-the-knee lesions. Both afore mentioned studies for the first time demonstrated a patency benefit of a drug-coated balloon over percutaneous transluminal angioplasty. Therefore, so far the use of drug-coated balloon in below-the-knee disease in daily practice was experimental and limited to “drug-coated balloon believers” that will not be changed by the present publication. In my daily practice I will still use the drug-coated balloon brand investigated in the two ACOART studies in long below-the-knee total occlusions. Interestingly, in IN.PACT DEEP, the to date only study with a published five-year follow-up using a “high-dose” drug-coated balloon, the composite endpoint consisting of all-cause death, major amputation, and clinically-driven target lesion revascularisation was identical for both study cohorts (drug-coated balloon 59.8% vs. percutaneous transluminal angioplasty 57.5%, p=0.309) as well as the all-cause mortality rate (drug-coated balloon 39.4% vs. percutaneous transluminal angioplasty 44.9%, p=0.727).”


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