Editorial Articles in JAHA Address Paclitaxel in PAD Studies
May 31, 2019—A series of editorial articles and letters published online in Journal of the American Heart Association (JAHA) continue to evaluate the data and discuss the conclusions regarding long-term mortality with paclitaxel-eluting stents and paclitaxel-coated balloons in the superficial femoral artery.
This concern was initially raised by the findings of a systematic review and meta‐analysis of randomized controlled trials (RCTs) evaluating paclitaxel-eluting stents and paclitaxel-coated balloons in peripheral artery disease, which found that an increased risk of death in the long term was associated with these devices when used in this anatomy. The study, “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," was published online in December 2018 by Konstantinos Katsanos, MD, et al in JAHA.
The recent editorial articles in JAHA include:
- "Is There a Real Association Between Paclitaxel Devices and Mortality? Time to Pause and Re‐Evaluate What We Know About This Statistical Finding" by Mehdi H. Shishehbor, MD, et al (online here)
- "Is Paclitaxel Causing Mortality During Lower‐Extremity Revascularization?" by Rajesh V. Swaminathan, MD, et al (online here)
- A letter by Stefano Bonassi, PhD, regarding the article by Katsanos, et al (online here)
- A response by Katsanos et al to Dr. Bonassi's letter (online here)
According to Shishehbor et al, the Katsanos et al meta‐analysis was well conducted overall, given the available data; however, it also had many limitations, including:
- It did not provide an explanation for or proof of a causal relationship, but rather a hypothesis‐generating statistical association.
- It was a summary-level meta‐analysis that did not include patient‐level data to adjust for clinical and angiographic differences between those who died and those who did not.
- Less than 50% of the included trials reported data beyond 1 year; one had 4‐year results, and only two reached the 5‐year time point.
- There were a significant number of patients lost to follow‐up who were not accounted for in the meta‐analysis.
- The study was conducted as an intention‐to‐treat analysis, and although this is the most valid approach to assess efficacy in RCTs, it does not represent the “true paclitaxel exposure” when assessing a safety signal, particularly because many of these trials had substantial crossover to the experimental treatment arm.
- The dose‐dependent relationship is likely to be flawed because the equation used to assess the paclitaxel dose/time relationship is thought to have overestimated drug exposure and its effect over time.
- Ultimately, the study findings could be by chance, a type‐1 error because of multiple testing, or hidden biases because of incomplete and unstructured follow‐up in these trials.
Shishehbor et al, stated, "Collectively, we believe Katsanos’s article represents nothing more than a statistical association with multiple explanations for the findings." They added, "However, if this statistical association is because of bias from clinical trial design, it is likely that any repeat analysis of the same data will find a similar association between paclitaxel use and mortality. Indeed, the recent FDA announcement revealed a preliminary association between paclitaxel devices and mortality."
In their article, Shishehbor et al supported the prioritization of safety endpoints, such as mortality, in current and future clinical trials evaluating paclitaxel‐coated devices and asserted that real‐world analyses like those from Medicare data are at least as relevant as RCTs.
Shishehbor et al also are concerned that an overreaction to the conclusions of the Katsanos meta-analysis and the FDA communication of March 15 could reduce the use of these devices to the detriment of public health. "At the present time we believe that the undisputed benefit of drug-eluting stents and drug-coated balloons outweigh their theoretical and uncertain risk," concluded Shishehbor et al.
Similarly, Swaminathan et al critiqued the scientific data behind paclitaxel‐coated devices in the context of recent mortality concerns and reviewed the newly generated patient‐level analyses and preclinical animal data on potential mechanisms of paclitaxel toxicity to address whether there is true causation or simply a correlation.
They questioned the idea of the increased deaths being necessarily related to the drug, stating, "The half‐life of paclitaxel is generally in the range of months. The peak plasma concentration occurs soon after the procedure and is thought to be below the level known to cause systemic adverse effects. For these reasons, one would hypothesize that any mortality linked directly to paclitaxel would occur sooner than the divergence in event rates seen at 2 years and beyond. The causes of deaths in the RCTs were also broad and included cardiovascular causes, infectious causes, pulmonary causes, and malignancy, among others. Establishing biological plausibility is difficult without a clear signal of one type of adverse event."
Swaminathan et al noted that the Vascular Leaders Forum and the FDA's upcoming Drug-Coated Balloon Safety Town Hall meetings are important steps to bring together stakeholders for open discussions as new data emerge. They advised, "In the meantime, a reasonable approach toward patient care is to use caution and have straightforward conversations with patients. Perhaps the same as low as reasonably achievable concept used for radiation protection should be applied herein (essentially, to use the lowest dose of paclitaxel necessary to get an effective result)." Additionally, they support continued research and development of nonpaclitaxel treatment strategies.
In his letter, Dr. Bonassi suggests that the possibility that the Katsanos meta‐analysis results are affected by some selection bias raises doubts about the real increase of all‐cause mortality in patients treated with paclitaxel‐coated devices. Dr. Bonassi noted that the FDA recommended that further research is required, and there is a need for data from extended duration of follow‐up in those studies that do not show higher risk of death in short‐term analyses.
In response to Dr. Bonassi, Katsanos et al acknowledged that a specific causal mechanism of the increased mortality remains unknown and few trials have collected long‐term follow‐up data. They note, however, that the availability of (or lack of) long-term data depend on the various starting points of the cited studies. They also have presented an updated meta‐analysis at 2 and 5 years with an increased sample of a predominantly claudicant population, which confirms a significantly increased risk of death with the use of paclitaxel‐coated devices in the femoropopliteal artery. Additionally, they cite data to demonstrate the contention that there was no evidence of systematic publication bias.
To see all of the articles in our continuing coverage of the paclitaxel safety data review, please visit this page.