Accepting the Risk of Treatment with Drug-Coated Balloons

What has been your reaction to the FDA’s June advisory committee meeting on paclitaxel-coated drug-coated balloons and drug-eluting stents late mortality?

The FDA panel meeting on June 19-20 in D.C. is obviously a very hot news item. I don’t believe much new data came out. The panel confirmed that there is a mortality signal, as did the original Katsanos meta-analysis¹. However, they as yet see no evidence of causality. Nevertheless, the FDA and European organizations have advised against using paclitaxel devices, certainly for the treatment of claudication. I think that is overreactive, because as I’ve said², though there appears to be a signal of higher mortality for patients treated by paclitaxel-coated devices as compared to non-coated devices, it remains to be seen whether that signal is a statistical quirk due to some other variable or whether it is due to some causality from the paclitaxel itself. As far as I can see, there is no evidence that causality exists, as yet. So perhaps the very strong reaction and the great interest in not using paclitaxel-coated devices is somewhat of an overreaction. At this point, after looking back at my years in practice, one always accepted the risk of a treatment and compared it to the benefits that treatment would provide. Any physician treating a patient with critical limb ischemia (CLI) accepts substantial risks in order to reverse the ischemia and save the leg. If one is treating a patient with very severe claudication, i.e., they can’t walk to the bathroom or can’t ambulate at all, clearly the risk of treatment is justified by overcoming that severe symptomology. On the other hand, if one is treating minimal claudication or lesions which aren’t producing real claudication at all, which has happened both in the hands of many vascular specialists, I question the value of using any stent or coated or uncoated balloon in these circumstances. Other, non-interventional treatments offer better ways to treat these patients, particularly if they have serious comorbidities. I don’t think we have conclusive evidence yet that the risk of mortality with paclitaxel is as big a deal as some people are making it out to be. That is my relatively conservative view on the matter.

The FDA did seem to confirm a possible signal with their own study.

There seems to be some confirmatory evidence in other analyses and the FDA did its own analysis. There are only 3 or 4 trials with very long follow-up, and the signal is only apparent after 2 to 5 years. The data is the data; there appears to be a mortality signal, but many other confounding factors could produce that signal besides causality. Until causality is demonstrated, my belief is that when a patient has serious enough symptoms or a limb-threatening condition, it is appropriate to take a risk that appears 2 to 5 years later, even if it is causal. So far, there has been no proof of causality, and as we know, patients, for cancer treatment, take much larger doses of paclitaxel without any evident mortality risk. I think it is still an open question. This paclitaxel mortality signal may not be real. It may be a statistical quirk in the meta-analysis. There are many issues that could be raised that would define it as a statistical quirk. We don’t really have good data on each patient and what other treatments they received, if they were followed up, and so forth, and that could influence mortality as well as receiving paclitaxel. It is a very important topic, and particularly so because industry has been appropriately aggressive in producing paclitaxel-coated devices, which clearly have a benefit in preventing restenosis and the requirement for reintervention. It remains an exciting, interesting topic that deserves the attention it is getting, but I am concerned there is an overreaction. When a patient needs treatment, one takes risks. The risks when we operated on these patients was substantial, that of dying or having a major complication. We took those risks because the benefit from our procedures was worth taking the risks for. The same may be true of paclitaxel-coated devices, if patients truly need a procedure. I believe claudication is rarely an indication for any invasive therapeutic procedure. That is just my bias, because it is a relatively benign symptom and the patients that have it almost always have associated other arterial atherosclerotic problems that limit their lifespan.

Is there a full understanding of the disease process of critical limb ischemia?

No. Critical limb ischemia doesn’t always mean that the patient is going to lose their limb. However, if the patient has advanced gangrene, advanced ulceration and infection, and true ischemia, that patient has critical limb ischemia and needs to be treated invasively. For 25-30 years, we have been preaching against the choir that most of these patients need interventions, either endovascular or operative, in order to save the limb. Over the years, we were regarded as crazy when we advocated that these very sick patients needed to have the limb saved if it was possible. We were really the father of invasive, aggressive treatment of critical limb ischemia. I believe risks need to be taken in that circumstance, because the alternative, limb loss, is so bad. Old, sick patients after a major amputation rarely are rehabilitated to the point of walking and they are often relegated to a chronic care facility because they can’t be taken care of at home. We are very aggressive in dealing with true CLI. There are some patients being diagnosed as having CLI with mild rest pain, which may not really be ischemic rest pain, and those patients may not need aggressive treatment. Real ischemic rest pain takes a little skill to diagnose and separate from other problems that older patients have that produce pain at rest in their extremities. Real ischemic rest pain, gangrene, ulceration due to ischemia, not due to infection — patients with these need aggressive treatment either with an endovascular procedure or with an open operation. It is a risk appropriately taken, in that circumstance. On the other hand, lots of patients have intermittent claudication and my belief is that many if not most of those patients probably don’t require invasive treatment. The tendency of late, both with interventional specialists and vascular surgeons, is to treat invasively most patients that present with intermittent claudication. I happen to think that is not so appropriate, but that is opinion, not fact. Over the years, I have rarely intervened on a patient for claudication, although I did so on occasion, when they couldn’t walk to the bathroom or were completely disabled. Those patients need treatment. The problem is that this is an area that everybody is interested in, because they have the skills to deal with it, but not everybody — either in vascular surgery or the interventional specialties — really understands the disease process.

Can you tell us about the alliance³ with the Cardiovascular Research Foundation (CRF) where VEITHsymposium has agreed to provide educational content at Transcatheter Cardiovascular Therapeutics (TCT) this fall and vice versa?

Dr. Enrico Ascher, co-chair at VEITHsymposium, has created two 90-minute sessions that will take place at TCT, one dealing with lower extremity ischemia and covering mostly critical limb ischemia, and one session dealing with aortic endovascular issues of interest. Those will be presented at TCT, which takes place September 25th-29th, and TCT is presenting two components at VEITHsymposium, taking place November 19^th-23^rd, that will be of great educational value to vascular surgeons. One component will be a pavilion where techniques can be practiced in a hands-on way over two days. This will include, among other things, teaching vascular surgeons how to better do radial artery access for other vascular bed procedures such as the lower extremities or renal artery interventions. Interventional cardiologists do radial artery access extremely well for heart and carotid disease. CRF will also be leading the effort and partnering with us on an innovation session for the better part of a day at VEITHsymposium. Vascular surgeons can become further educated in some of the technical aspects of endovascular treatment, thanks to our alliance. We are also hoping that many interventional cardiologists will attend VEITHsymposium, because they can learn from our content focusing on lower extremity ischemia, carotid disease, and so on. As always, we intend to offer up-to-date state-of-the-art education in treatment options for all aspects of non-cardiac vascular disease. Ultimately, the goal of the alliance is to provide better patient care through better education of both vascular surgeons and interventional cardiologists.

Disclosure: Dr. Veith reports no conflicts of interest regarding the content herein.

Dr. Frank Veith can be contacted at fjvmd@msn.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. Veith FJ. Comments on the current crisis with paclitaxel eluting lower extremity endovascular devices. J Cardiovasc Surg (Torino). 2019 Jun 4. doi: 10.23736/S0021-9509.19.11031-2. [Epub ahead of print]

3. CRF and VEITHsymposium Announce an Alliance Between Transcatheter Cardiovascular Therapeutics (TCT) and VEITHsymposium. June 19, 2019. Cath Lab Digest. Available online at https://www.cathlabdigest.com/content/crf-and-veithsymposium-announce-alliance-between-transcatheter-cardiovascular-therapeutics-tct-and-veithsymposium. Accessed June 19, 2019.