Polymer-free Drug Delivery to the Vessel Wall: A Drug-eluting Balloon Catheter

Can you briefly describe the Paclitaxel-Eluting PTCA balloon catheter in Coronary Artery Disease (PEPCAD)-I SVD and II-ISR trials? These two trials follow a pilot study done by Scheller et al, published in the New England Journal of Medicine1 in 2006. Dr. Scheller compared plain old balloon angioplasty with a paclitaxel-eluting balloon in a small cohort of patients with in-stent restenosis. He found that patients who received the drug-eluting balloon had both significantly lower restenosis rates and major adverse cardiac events (MACE) such as myocardial infarction, bypass surgery, repeat angioplasty or death. PEPCAD I-SVD, the first of two studies I presented at TCT earlier this year, evaluated the use of a drug-eluting balloon catheter (SeQuent Please, B.Braun, Melsungen, Germany) for the treatment of small vessel coronary artery disease in 120 patients. PEPCAD I-SVD is a one-arm study, looking at the drug-eluting balloon as the first-option device to treat small vessel disease. If the result was not satisfactory, the subjects could be treated with any device, but a bare metal stent was recommended. After six months, de novo lesions treated solely with the drug-eluting balloon showed a 5.5% binary restenosis rate and 6.1% MACE rate. In PEPCAD II-ISR, we directly compared the drug-eluting balloon catheter to the paclitaxel-eluting Taxus stent (Boston Scientific, Natick, MA) in 131 patients over six months for the treatment of in-stent restenosis. PEPCAD II was designed as a two-arm, prospective, randomized, controlled study. In the first arm, the drug-eluting balloon was a standalone device, but in some cases (10.3%), a stent had to be used if the initial result was unsatisfactory. The second arm of the trial was the assignment to the paclitaxel-eluting Taxus stent. In 6.2% the stent did not cross the lesion and a balloon catheter had to be used instead. Patients treated with the drug-eluting balloon experienced a 3.7% in-stent restenosis rate and 4.8% MACE rate, as compared to patients receiving the drug-eluting stent, who experienced an in-stent restenosis rate of 20.8% with a 22.0% MACE rate. Is this the first time this device has undergone a randomized clinical trial? Well, yes and no. The prospective, randomized PACCOCATH ISR I and II trials, also presented at the TCT by Dr. Scheller, used a drug-eluting balloon featuring the same concept, but produced by a different manufacturer (Paccocath, Bavaria Medizin Technologie, Germany). I do want to make a clear distinction between both the Paccocath and the SeQuent Please balloons on the one hand and another paclitaxel-eluting balloon catheter (Eurocor, Bonn, Germany) which uses a different technology to deploy the drug to the vessel wall. To our knowledge, no clinical data-based testing in humans have been published yet, and some of the brochures that indicate clinical information show data that are identical with those from the PACCOCATH study. Why might a balloon work better than a stent for drug delivery? First, the dose applied to the vessel wall by the balloon catheter is about three times higher as compared to the drug-eluting stent. Second, the balloon distributes the drug homogenously along the arterial wall, whereas in drug-eluting stents, the highest concentration is underneath the struts. Third, when a stent is deployed into the artery, usually the device stays there forever. Especially with the polymers, stents may be associated with a permanent alteration of the vessel wall. When a balloon is used, no foreign body remains behind. Still, based on the mechanism of restenosis, some situations do exist where you require a stent. I am not suggesting it is now all about the balloon and that we do not need stents anymore. The drug-eluting balloon will very likely be another device in our toolbox, but a sophisticated one. We most probably will end up with particular approaches and particular devices for particular types of lesions and patients. Moreover, I think there are also some general reasons why people would prefer a balloon over a stent. A balloon is a device that can be handled a little more easily than a stent, since it is thinner and more flexible than a balloon catheter carrying a stent. Second, there may be some financial advantage. For small vessel disease and in-stent restenosis, at least, it appears that the drug-eluting balloon is superior to the drug-eluting stent. In what other types of lesions might a drug-eluting balloon be appropriate (or not)? The paclitaxel-eluting balloon catheter may be especially beneficial in complex situations such as acute myocardial infarction, bifurcational lesions, and in patients with diabetes and or elevated white blood cells as a reflection of enhanced inflammation. However, other indications will be evaluated as well. In vascular dissection, cardiologists will still use stents; however, they may either deploy the stent using the paclitaxel-eluting balloon catheter or dilate the vessel with the drug-eluting balloon following stent placement. The primary endpoint for both trials was 6-month late lumen loss. Why this endpoint instead of MACE? First of all, it is a statistical reason when designing studies. Six-month late lumen loss is a continuous variable. In order to detect a difference in a small trial, that is always a good thing to do. MACE, however, from a clinical perspective, is what really matters. The ultimate proof would be MACE, and we in fact did not observe any differences in MACE early on, i.e., after 30 days. However, we do observe significant differences after 6 months. Perhaps we will see a more pronounced difference after one year and three years. That is why this long follow-up period is part of the study design. There was some discussion at the TCT news conference regarding the use of late loss in PEPCAD I and II. It was argued that late lumen loss as an endpoint probably does not make too much sense because the late loss would be related to the amount of luminal gain during the procedure. Stents provide a greater luminal gain than balloons. If this statement was correct, and I do not think it is across devices, then I think the easiest thing to do to correct such a problem would be to not expand the stent as much instead of a 0.3 stent expansion, perhaps 0.15 mm in order to appropriately compare late lumen loss between stent and balloon. Nonetheless, we picked up the cue and will perform the suggested and some additional analyses in this regard in order to reach more clarity. Certainly, late lumen loss is different in balloons and stents. We will always compare apples and oranges because balloons and stents are different. However, they should not be seen as mutually exclusive; they are different arrows in the same quiver serving different purposes. You mean there are other issues besides the initial gain that may affect the amount of late lumen loss. Yes, for one reason, there is a polymer on many stents. With a drug-eluting balloon, you avoid that issue. There was a low restenosis rate in PEPCAD I-SVD. Considering the excellent drug coverage provided by the balloon, could operator issues play a part in contributing to the restenosis rate? PEPCAD I-SVD had a 5.5% restenosis rate without additional stenting, which is very low. That is an absolutely great number. One has to be aware that we talk about a pilot study with a relatively small number of subjects. But in general, having analyzed a couple of thousand angiograms in a quantitative angiography lab, I definitely do agree that the results are highly operator influenced. That is why I think the gold standard is still the prospective, randomized, controlled study design. I would also suggest using the same core lab in order to allow for an accurate comparison. This of course puts a question mark behind any historic comparison. Still, PEPCAD I’s 5.5% restenosis rate apparently puts the paclitaxel-eluting balloon catheter far ahead of many other products, which are associated with higher restenosis rates. I do not know whether the sponsor or someone else in the future will decide to run a prospective trial in small vessel disease comparing this drug-eluting balloon against some other interventional method. Unfortunately, that is not my call. I may only advise. What did you think about the outcome of the PEPCAD II-ISR trial? The balloon was superior when compared to the drug-eluting stent. It was a randomized comparison, it was a fair comparison. Whenever we decided we would exclude a patient for enrollment violation, we did so after the documents and CD of the initial procedure were available. So from the process point of view, the evaluation was well-executed with no bias. PEPCAD II-ISR shows the difference. It is a relatively small study with 60 versus 70 subjects in the as-treated evaluation. The data are clear. I hope they can be confirmed in a larger cohort where the limitations of a pilot study do not apply. Has the PEPCAD-II trial in particular received a fair reception, especially since the balloon did so well against the drug-eluting stent? First of all, I am always happy if someone scrutinizes our data, and challenges our data, because ultimately we want to help the patient. I actually expected more reservations. Our data were well received. On the other hand, if we take the PACCOCATH I and II trials by Dr. Scheller, THUNDER (which was in the peripheral arteries) by Dr. Teppe, and now PEPCAD I and II, the evidence is accumulating that this concept of drug-delivery to the vessel wall seems to work. Usually with a new concept, people are very enthusiastic, then they bounce back down before leveling off somewhere between the very optimistic and the very reserved positions. The device shows promising results and the data are surprisingly consistent in favor of the balloon surprisingly in that we see a 0.19 mm late loss compared to a 0.18 mm late loss with both of the trials when using the paclitaxel-eluting balloon alone. We also observe a significant difference comparing the balloon to the Taxus stent. The Taxus stent actually fared a little bit worse than I thought it would in such a study. However, PEPCAD II-ISR is a prospective, randomized, controlled study and our data do not indicate a difference in baseline characteristics or any other bias. Ultimately, the balloon is a promising device. We simply need more data. The outcomes so far are not only a justification, but a clear indication that we should conduct more trials and obtain more clinical data. If these results can be confirmed in other studies, this paclitaxel-eluting balloon catheter would have a significant impact on patient care, in favor of the patients. However, I do caution about transferring the data to any other drug-eluting balloon catheter (although any additional technology is welcome). What are your future plans? We will be working on collecting and computing the data from the two PEPCAD trials for peer-reviewed publication. There is one currently active trial, PEPCAD III, which is comparing the combination of a drug-eluting balloon and a stent in comparison to a drug-eluting stent. That is the only PEPCAD trial in which we are not involved as of today. There is also a study in diabetics, which is a randomized prospective study conducted in Asia, and another small, preliminary feasibility pilot study in subjects with bifurcated lesions, using the SeQuent Please balloon. These trials should give further indication if we are on the right track. The results of these studies will also allow us to plan a larger study in respect to one important issue, which is clopidogrel. What has not been emphasized to an adequate extent is that clopidogrel medication with the balloons was administered for shorter period of time than with stents. Right now the recommendation after paclitaxel-eluting stent deployment is around 12 months. In the PEPCAD trials, we used the drug only for 1 and 3 months with the balloon patients. So far, we have not seen any late thrombosis in more than 200 patients. This is also true for the PACCOCATH studies reported by Dr. Scheller. We may significantly save on clopidogrel administration, therefore also saving on cost and adverse events as a side effect of clopidogrel. Combining all the short-term studies together before beginning a longer, larger study, we could hopefully come up with a more precise idea as to what the duration of the clopidogrel medication should be. Ultimately, the drug-eluting balloon is an additional and promising approach, which cardiologists could use for treating their patients with coronary artery lesions, especially in the light of the current, vibrant debate about late thrombosis about when using drug-eluting stents. None of the device manufactures should claim exclusivity. No single approach treats all. However, if the concept would work as our data indicate, exhibiting promising clinical and angiographic results, financial benefits on the reimbursement side may also ensue. So this comes at the right time, and we will be happy to listen to anyone with suggestions about what we should and could do going forward. Dr. Unverdorben can be contacted at sbu135@comcast.net.

Recommended Reading 1. Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006 Nov 16;355(20):2113-24. Epub 2006 Nov 13.