A View on Drug-Coated Balloons From the Land of the Practicing Physician

On June 19 and 20, 2019, the Circulatory System Devices Panel of the Medical Devices Advisory Committee convened to discuss and make recommendations on information related to recent observations of increased long-term mortality in peripheral arterial disease (PAD) patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents compared to patients treated with uncoated devices. The Food and Drug Administration (FDA) requested advisory panel input regarding the presence and magnitude of the excess mortality signal as well as potential causes of the signal. They additionally requested input regarding appropriate regulatory actions in light of the findings. Ultimately, while the advisory panel generally agreed that there was a possibility of excess late mortality risk, they also concluded that there was definite short-term benefit of these devices regarding quality of life improvements and avoidance of target lesion revascularization procedures. Based on these conclusions, the FDA now plans to digest this information and make recommendations regarding possible changes to product labeling, indications for use, and future trial designs.  

The FDA’s chosen path forward is largely based on what is believed to be factual meta-analysis results.¹ However, this meta-analysis is highly flawed. It utilized statistical methods and low-quality data that raised more questions than it answered, a sentiment that was unanimously echoed by the advisory panel. Unfortunately, publication of the meta-analysis with its overzealous conclusion created doubt in the minds of physicians, administrators, and regulators regarding the safety of these devices, despite the fact that no mortality signal was detected in large, real-world registries that are more representative of the patients that we treat in everyday practice. Now, the FDA must take a stand that is believed to be in the best interest of patients, despite the fact that it remains unclear whether there is real excess mortality risk or whether the mortality signal is related to reasons such as statistical chance, study design factors, prior paclitaxel exposure, or incomplete follow-up data, to name a few. For these reasons, the “dear doctor” warning letters that were released by the FDA on January 17th and March 15th have not affected my practice.

An interesting fact that was repeated during the committee meeting was that the most common cause of malignant death in the small number of deceased patients was lung cancer. A recent publication by Mustapha et al² compared the mortality of 22 cancers vs critical limb ischemia (CLI) at 5 years and found the most common cause of death by far was lung cancer (Figure 1). The second-most common cause of death was CLI. Our figure is based on almost 24,000 patients from the Centers for Medicare & Medicaid (CMS) database of patients who received a first diagnosis of CLI, and was compared to patients following first diagnosis of cancer as reported by the Centers for Disease Control and Prevention (CDC). Therefore, the finding that most malignant deaths in paclitaxel-treated patients were due to lung cancer is no surprise, since this is the leading cause of malignant death in the United States. 

Compared to all of these cancers, including the “deadliest cancers” (i.e., pancreas, liver, lung, esophagus, stomach, brain, and ovary), CLI is the second most common cause of death, largely because the disease is common and deadly. How has CLI remained under-recognized for so long that it has now become more deadly than all cancers, except lung cancer? It therefore seems that we have more serious, urgent issues to discuss and address a solution toward. I urge regulators to take a step back and see the bigger picture before providing recommendations that might in some way hinder a patient’s ability to receive a potentially life-saving treatment.

Drug-coated technologies must continue to be made available without additional restriction for the sake of our patients and because of overwhelming evidence regarding the quality of life benefits they offer. Regardless of future FDA guidance on this topic, we practicing physicians will have to carry the burden of what is right for our patients, despite the fact it might leave many of us, as practicing physicians, vulnerable to a low chance of possible lawsuits. Overall, I will do what is right for our patients and continue to use one of the greatest advances in PAD/CLI therapy: drug-eluting technology. 

Disclosure: Dr. Mustapha reports he is s consultant to BD, Boston Scientific, Medtronic, Philips, and Terumo. 

Dr. Jihad Mustapha can be contacted at jmustapha@acvcenters.com.

REFERENCES

1. 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.

2. Mustapha JA, Katzen BT, Neville RF, Lookstein RA, Zeller T, Miller LE, Driver VR, Jaff MR. Critical limb ischemia: a threat to life and limb. Endovascular Today. 2019 May. Available online at https://evtoday.com/2019/05/critical-limb-ischemia-a-threat-to-life-and-limb/. Accessed June 20, 2019.

3. Secemsky EA, Kundi H, Weinberg I, Schermerhorn M, Beckman JA, Parikh SA, Jaff MR, Mustapha J, Rosenfield K, Yeh RW. Drug-eluting stent implantation and long-term survival following peripheral artery revascularization. J Am Coll Cardiol. 2019 May 28; 73(20): 2636-2638. doi: 10.1016/j.jacc.2019.02.020.