For many years following their commercialization, drug-coated balloons (DCBs) and drug-eluting stents (DES) represented rapidly growing multimillion-dollar peripheral vascular markets, in which a number of medtech industry giants—such as Medtronic, Boston Scientific, BD, Cook Medical, and Philips Healthcare—had made substantial investments to support their devices with clinical data.
In recent months, however, significant concerns have been raised with regards to the safety of paclitaxel-based DCBs and DES, with some evidence showing that these products may be associated with higher mortality rates in peripheral artery disease (PAD) patients.
Below, our market experts outline recent developments surrounding this controversy and explore how markets have reacted thus far, as well as what industry players may expect going forward.
The Katsanos Study vs. Other Data: Are Paclitaxel-Based Devices Safe?
In December 2018, a published meta-analysis (henceforth referred to as the “Katsanos study”) raised serious concerns surrounding the long-term safety of using paclitaxel-based devices—specifically DCBs and DES, which both use paclitaxel as an anti-restenotic drug—in the treatment of PAD; in particular, the study found that the use of these paclitaxel-based products in the femoropopliteal artery was associated with a heightened risk of mortality in PAD patients 2 to 5 years following treatment. Consequently, several major trials, including SWEDEPAD1, SWEDEPAD2, and BASIL-3, halted patient enrollment to ensure patient safety.
However, because the Katsanos study was based on trials that lacked patient-level information, it was difficult to positively ascertain whether the placement of the paclitaxel-based devices was the actual cause of mortality observed in the meta-analysis; since its publication, the meta-analysis results have been challenged by numerous other studies and a number of competitors insisting that their devices are safe.
For instance, two weeks following the publication of the Katsanos study, six-month data pooled from 355 patients in the THUNDER, FEMPAC, PACIFIER, and CONSEQUENT trials demonstrated the safety and superiority of DCBs over plain angioplasty balloons; 2-year data from these trials, also showing positive results, were released in March 2019. Moreover, medtech giants Medtronic and Boston Scientific further challenged the Katsanos results by announcing that a “deep dive” into their own data did not reveal the safety concerns that were raised in the Katsanos study, shedding additional doubt on the contentious findings.
Despite these efforts, the FDA issued a letter in January 2019 informing peripheral interventionalists and vascular medicine physicians that the agency is evaluating the information surrounding the safety claims made in the Katsanos study.
Meanwhile, DCB and DES companies continued to insist on the safety of their devices, producing clinical evidence to challenge the aforementioned claims. For example, at LINC 2019, Medtronic and Philips Healthcare showcased long-term patient-level safety data supporting their respective IN.PACT Admiral and low-dose Stellarex DCBs. Additionally, in April 2019, Cook Medical released 5-year patient-level data from its randomized controlled trial on the Zilver PTX DES, which enrolled 479 patients in the US, Germany, and Japan. Though the trial does not support or discredit ongoing investigations, the company had released the data to showcase transparency and to demonstrate the company’s commitment to continued collaboration with researchers to improve patient outcomes.
Regulatory Agencies and Vascular Associations Respond
Ultimately, a special Vascular Leaders Forum (VLF) was called in March 2019 to discuss the Katsanos study results. At this forum, physicians, manufacturers, and representatives of regulatory bodies held discussions to explore various scenarios in which paclitaxel were used in order to determine if paclitaxel-based devices are in fact associated with any long-term safety risks.
Because the forum found no data that show pharmacokinetic or toxicity concerns associated with the use of low doses of paclitaxel in DCBs and DES for PAD, it was difficult to draw any major conclusions on whether paclitaxel-based devices were the actual cause for increasing mortality. Notably, the FDA—which was represented at these talks—revealed that its preliminary review did signal some mortality risk associated with paclitaxel-coated devices; however, the agency also noted that it recognized the limitations of currently available data and that it was in the process of replicating the Katsanos study through a process that relies on all randomized clinical trials (RCTs) and statistical methods used in the original meta-analysis as well as alternative approaches and methodologies.
Moreover, the FDA also announced an advisory committee to conduct an individual patient-data analysis to establish the safety profile of these devices; until this concludes, the FDA has recommended using alternative treatment options to paclitaxel-based DES and DCBs.
Though the VLF forum did not produce any concrete or definitive conclusions, it is expected that the discussions that took place will spur a number of ongoing and future clinical trials to ensure that all major safety parameters and patient details are considered for analysis.
Several other physician societies and regulatory bodies have formed advisory committees to conduct reviews with respect to the alleged mortality risks associated with paclitaxel-based devices in the treatment of PAD. For example, UK’s MHRA recently announced the formation of an advisory committee composed of specialist physician societies, including experts on toxicology, medicine, and statistics, major regulatory bodies like NICE, the British Society of Interventional Radiology, and clinical stakeholders for the BASIL-3 trial. This committee will review the existing evidence surrounding paclitaxel-based devices in order to advise some form of regulatory action.
How the Market Has Reacted
The major competitors in this space, including Medtronic, Boston Scientific, BD, and Cook Medical, have all continued to make efforts to support and promote the safety of their devices. In the US, these efforts—as well as the prevailing efficacy information—were enough to offset the potential negative impact of the original Katsanos study, as DRG's PriceTrack database showed that DCB and DES sales for Q1 2019 remained strong through February. We will continue monitoring this market throughout Q2 to evaluate whether or not the FDA's warning letter moved physician opinion more than the initial study.
Source: Pricetrack, DRG, 2019
The situation in Europe may unfold differently, however. Interviewed vascular physicians in Europe appeared hesitant to use paclitaxel-based devices in the treatment of PAD; these physicians indicated that they would be more comfortable using alternative options, like uncoated PTA balloons and stents, until the concerns raised surrounding the long-term safety of paclitaxel-based devices are resolved. This sentiment was echoed by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), which released a statement in April this year recommending that physicians use alternatives to DCBs and DES for the recanalization of lower limbs until any definitive results demonstrate the safety of paclitaxel-based devices.
Moreover, expert panels at the 2019 Charing Cross International Symposium indicated through a vote that, while they do not consider the use of paclitaxel-based devices for PAD treatment to be explicitly dangerous for the time being, they will reserve their full judgement until conclusive data is published by the FDA and MHRA.
Until a conclusion is established on the safety of paclitaxel-based devices, it will be difficult to discern how the market will react. As it stands, the impact on Q1 sales has been minimal, largely because the regulatory warnings on paclitaxel-based devices emerged in Q1 2019.
The outcome in the US and across Europe will be primarily dependent on the conclusions drawn from the ongoing FDA and MHRA reviews. The FDA, for one, has scheduled a public meeting on June 19th to discuss the use of paclitaxel-based devices in PAD patients, and it is likely that this meeting will be used to provide more definitive information on usage guidelines and recommendations, which may determine how the market reacts for the rest of the year.
Looking forward, medtech companies in the PV space should continue to consider the following questions as the story develops:
- What has been the impact of the Katsanos study on paclitaxel-based device usage in treating PAD?
- Are there geographical differences in how the Katsanos study is being received?
- What are some key events on the horizon?
- Given the historically strong efficacy data surrounding these devices, will physicians stop using them even if regulators do not ban them?
Interested in more data and expert perspectives around the paclitaxel controversy?
DRG experts are staying on top of the latest updates and market impact.
Contact us with your questions:
- Ashish Bhupal, Manager, Medtech Insights
- Zaid Al-Nassir, Senior Analyst, Product Support