By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: A newly published meta-analysis of randomized, controlled trials concerning paclitaxel-coated balloons and stents in femoral popliteal disease patients revealed a marked increase in all-cause death at two and five years.

SOURCE: Katsanos K, Spiliopoulos S, Kitrou P, et al. 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;7:e011245.

Endovascular treatment of occlusive arterial disease of the leg has been increasing steadily over time. The femoral and popliteal arteries remain the most common sites of involvement. However, interventional treatment is marked by high rates of restenosis and target vessel failure. Drug-eluting stents (DES) and drug-coated balloons (DCB) have emerged as tools to improve patency outcomes in these vessels, with paclitaxel representing the most common anti-restenotic agent in this arena. Numerous randomized, controlled trials (RCTs) have demonstrated that devices delivering this drug effectively reduce restenosis and target lesion revascularization in the leg. Several paclitaxel DCB and DES devices have been approved for use in the United States and in Europe.

A new meta-analysis of paclitaxel-eluting devices for treatment of femoral popliteal disease revealed that while all-cause mortality was similar between paclitaxel and control groups at one year, follow-up data at two years and five years show striking increases in all-cause death. Prompted by hints of increased mortality in a small number of RCTs with longer-term follow-up and by a single below-the-knee study that demonstrated higher rates of major amputations in the paclitaxel arm compared with control, Katsanos et al sought to identify high-quality RCTs of paclitaxel devices in the treatment of the femoral and popliteal arteries. Ultimately, the authors analyzed a collection of 28 RCTs that included 4,663 patients. Of these studies, four used a paclitaxel DES. The remaining 24 RCTs used paclitaxel DCBs.

The authors of each included RCT reported all-cause death out to one year, with a nearly identical 2.3% crude risk of death in both the paclitaxel and the control arms among the included subjects. The authors of 12 of the 28 RCTs reported all-cause death out to two years, totaling 2,316 patients. Availability of five-year data was much more limited, with only three RCTs (n = 863 patients) comprising this part of the analysis. At two years, the crude risk of death was 7.2% and 3.8% in the paclitaxel and control arms, respectively (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.15-2.47). At five years, the risk was 14.7% and 8.1%, respectively (HR, 1.93; 95% CI, 1.27-2.93).

The two-year numbers correspond to a 68% relative risk increase in all-cause death with paclitaxel-coated devices compared with standard balloons, with a number-needed-to-harm of 29. At five years, the relative risk increase was 93%, with a number-needed-to-harm of just 14. Interestingly, higher dosages of paclitaxel appeared to correlate with a greater risk of mortality. In a meta-regression analysis of the absolute risk difference of all-cause death against exposure to paclitaxel expressed as the dose-time product, there was a highly significant association between paclitaxel and the absolute risk of death.

The authors concluded that their data demonstrated a credible and large relative increase in longer-term all-cause death after exposure to paclitaxel-eluting balloons and stents for treatment of arterial disease of the upper leg. They labeled their results “alarming” and postulated that late paclitaxel toxicity may be responsible for their findings, calling for more study with longer-term follow-up.


The finding of a late increase in mortality with this entire class of otherwise-promising therapeutic agents certainly is unexpected. To many in the field, the conclusions lack a mechanistic explanation and strain credibility. However, that is not the inference of the field as a whole. In response to this study, the creators of two ongoing investigations of paclitaxel-containing devices in peripheral artery disease (PAD) — the BASIL-3 and SWEDEPAD 1 and 2 trials — have elected to halt enrollment pending further information.

On the mechanistic side, Katsanos et al noted that paclitaxel devices designed for use in the periphery are fundamentally different from those previously deployed in the coronary bed. For example, on average, devices designed for use in the femoral popliteal arteries contain more than an order of magnitude higher level of paclitaxel compared with the coronary Taxus stent. The drug-coated balloon paradigm results in significantly greater levels of a crystalline form of the drug released into the systemic circulation.

For now, it is difficult to know what to do with these data in the context of devices that have made their way into mainstream use and that represent some of the most effective technologies for treatment of PAD of the leg. Most authorities have cautioned against an overreaction. In the short term, making patient-level data from the individual trials available may allow for a better understanding of the profile of patient deaths over time and provide a greater level of knowledge. Ultimate answers may not be achieved without further trials and longer-term prospective follow-up. In either case, we are certain to hear more about this issue in the coming year.