CX 2020 LIVE came to life online—despite COVID-19—using state-of-the art broadcast technology to bring together more than 1,000 vascular specialists, live, from 95 countries across the world. The first session of the highly interactive conference, designed to deliver global vascular education in the CX style, saw participants from Stockholm to Santiago asking questions and engaging with leading vascular figures on the ongoing investigation into the safety of paclitaxel devices in the treatment of peripheral arterial disease (PAD). The session can now be viewed on demand here.
Roger Greenhalgh, MD, of London, chaired the event, with Andrew Holden, MD, of Auckland, New Zealand, moderating the panel discussion. Six speakers gave their five-minute presentations, with each talk interceded with five minutes of discussion time.
A historic occasion for vascular education, attendees can earn continuing medical education (CME) points through their presence at this virtual event, taking place every Tuesday and Thursday from 4 p.m.–5:20 p.m. BST from May 25 through to June 25.
Podium first: “Paclitaxel devices are associated with improved survival” in new propensity score-matched analysis of claudicants and CLTI patients
“The debate on the safety and efficacy of paclitaxel continues to rage,” Sapan Desai, MD, a vascular surgeon in Chicago, stated, kicking off the first session of CX 2020 LIVE with his podium 1st presentation on paclitaxel survival results related to drug-coated balloons (DCB) and drug-eluting stents (DES) out to five years. Contrary to the findings of Konstantinos Katsanos, MD, of Patras, Greece, et al in late 2018, Desai concluded that “paclitaxel devices are associated with improved survival, starting at nine months.” However, he added the usual caveat that “additional analyses, such as a more detailed subgroup evaluation, and causal inference determination, are urgently needed.”
In this propensity score-matched analysis, Desai and his co-investigators utilized a global healthcare registry to identify patients with femoropopliteal artery disease who subsequently underwent an endovascular intervention between 2010 and 2015. These patients—11,710 of whom underwent drug-coated balloon (DCB) or drug-eluting stent (DES) treatment, and 76,007 of whom underwent routine angioplasty or bare metal stenting—were followed for up to five years. In total, 61.5% of the paclitaxel cohort and 62.7% of the control group had chronic limb-threatening ischemia (CLTI), respectively.
There was no difference in the rate of periprocedural complications between the paclitaxel-treated group and the control group, the investigators reported. Desai related how patients treated using paclitaxel “have a lower rate of reintervention at one year, with a significant decrease in major amputation rate at five years.”
Additionally, the triallists found that mortality is significantly lower for claudicants, starting at nine months. At five years, 42.9% of paclitaxel-treated patients had died, compared to 59.2% in the control group.
COMPARE trial highlights efficacy of low-dose paclitaxel balloons
Sabine Steiner, MD, of Leipzig, Germany, told the CX 2020 LIVE audience that the COMPARE trial, the first head-to head comparison of two paclitaxel-coated DCBs, the COMPARE trial, showed “excellent efficacy” at one year in both arms. There was a similar patency at one year with the low-dose (2µg/mm2) Ranger DCB (Boston Scientific) compared with the higher dose (3.5µg/mm2) IN.PACT Admiral DCB (Medtronic).
While earlier meta-analyses have suggested an association between paclitaxel dose and late mortality risk, Steiner told the CX 2020 LIVE audience that the COMPARE trial results “cannot identify any signal for a relationship between paclitaxel dose and mortality, at one year or beyond.”
The COMPARE trial, published in the European Heart Journal, was a prospective, randomized, non-inferiority trial of high- versus low-dose paclitaxel DCBs for femoropopliteal interventions. All patients enrolled in the study had PAD categorized as Rutherford class 2–4.
The trial met both its primary efficacy (primary patency through 12 months) and primary safety (freedom from major adverse events through 12 months) endpoints. Steiner says that the investigators, led by Dierk Scheinert, MD, of Leipzig, Germany, “will follow the patients up to five years by telephone calls in order to gain safety information.”
Focusing on all-cause mortality, Steiner noted that the COMPARE trial data show “an overlapping of Kaplan-Meier curves through four years,” indicating “no signal for any relevant difference [between the two different paclitaxel dosages] with respect to mortality.” She continued: “Actually, death rates are rather low. After two years, where we do have quite a good follow-up, we observe a death rate which is around 3%.”
When looking at individual causes of death, Steiner shared that the research team did not see any “clear signal of an excess rate of a specific cardiovascular or non-cardiovascular death subtype.
“Importantly,” she expanded, “the same holds true, or we see a similar pattern of causes of death, for the six patients who died in the high-dose DCB group. Importantly, no death was considered procedure- or device-related by the clinical events committee.”
Speaking as co-moderator of the session alongside Roger Greenhalgh, Andrew Holden praised Steiner for bringing “new information that we are seeing for the first time” to CX 2020 LIVE.
Prompted by a question from Greenhalgh, Steiner clarified that the COMPARE trial was never designed to compare mortality between the Ranger DCB and the IN.PACT Admiral DCB, but rather efficacy. “What I would really like to highlight,” she stressed, “is that we have these meta-analyses showing us a signal that even for efficacy there will be a difference with respect to dose, so a higher dose will be more efficient. This was really the background of the COMPARE trial, that we wanted to have a non-inferiority design with respect to efficacy and primary patency. Here, we did not see a difference, which is really in contrast to the results from the meta-analyses.”
Holden, who was one of the authors of a 2019 paper published in the Journal of Endovascular Therapy (JEVT) refuting the idea of there being a dose-dependent impact of paclitaxel devices, said he “entirely” agreed with Steiner’s conclusions, adding: “I think it [the dose model] is the weakest part of the original [2018, Katsanos et al] meta-analysis.” Addressing Steiner, he said, “You have really shown that a low-dose device is as efficacious [as a high-dose one], and that there is no safety advantage or disadvantage.”
Steiner acknowledged that although she and her colleagues did not observe a signal with respect to mortality, the numbers in the COMPARE trial “are clearly very small in general, so there is a low mortality rate—we are definitely not powered for this question [detecting an association between increased mortality risk and paclitaxel dose].”
Therefore, the COMPARE trial can make “no statement about dose and mortality,” Greenhalgh concluded.
CX 2020 LIVE audience split over importance of dose effect
Polling during the CX 2020 LIVE session asked the audience: “Do you consider paclitaxel dose level to be crucial?” This split the CX audience with 53% of respondents voting “yes,” sharing their belief that paclitaxel dose levels are crucial.
FDA assessing “totality of evidence,” calls out specific value of individual patient-level data sets
Providing an update on the paclitaxel late-mortality signal from the Food and Drug Administration (FDA) perspective, Misti Malone, PhD, of the Center for Devices and Radiological Health at the FDA, said that the agency is in the “signal discernment/refinement phase” of the ongoing investigation.
Following the FDA Advisory Committee Meeting last summer (June 19–20, Washington, D.C.), approved paclitaxel devices have remained on the U.S. market with labelling updates that discuss ongoing uncertainties regarding the signal, as well as the conclusions of June’s meeting. At the time, the agency agreed that the mortality signal existed, but that the signal magnitude was uncertain.
“Because patient comorbidities, extent of disease, and lesion characteristics play a role in clinical outcomes, [the] FDA believes it is important for physicians to determine what patients are considered [at] high risk of restenosis, and they have a favorable risk–benefit profile from treatment with paclitaxel-coated devices.”
Clinical trials are continuing with revised informed consent and increased patient follow-up. Additionally, the FDA has also promoted efforts to increase trial robustness, such as attempts to reduce “missingness.” “We continue to collaborate with investigators of observational datasets, and through groups such as RAPID, a multi-stakeholder collaboration made of clinicians, industry members, and regulators aiming to improve the real-world evidence ecosystem, from data collection to analysis,” Malone explained. “These collaborations may provide insights into remaining questions, such as the precise magnitude of the signal, the mechanism for late-term mortality, and the benefit–risk profile in real-world patient populations.”
Malone stressed the importance of collaboration, finishing by saying: “This is a global issue that requires global collaborations.”
Referencing Desai’s earlier presentation on what he described as “another large, population-based study that failed to show a [mortality disadvantage], but in fact showed a mortality advantage of paclitaxel,” moderator Holden said he has found large population-based studies “reassuring,” and asked for the FDA’s thoughts on these types of analyses.
“We value the totality of evidence,” Malone replied, “be it from randomized controlled trials, single-arm trials, or observational datasets. The devil is in the details for many of these trials, in which we identify how many patients have been followed-up to four or five years, which is when the signal was noticed in our data sets. Many of these data sets have up to 50% missingness at this point, and although we may assume missingness accepts some level of randomness, it may not, so we typically need very robust, high-quality data with long follow-up in order to discern this mortality signal. So, we do value these observational datasets, and as part of the RAPID group, we are compiling all of the datasets we are aware of, and looking at the level of evidence and our confidence in the data that has been evaluated.”
Specifically commenting on individual, patient-level analyses, such as the VIVA individual patient-level data (IPD), Malone said: “We find those very valuable because we can dive into the details, we can see how the individual patients are affected, rather than looking at summary data. The higher-level meta-analyses help to guide us to our next step to do a more in-depth analysis.”
“High impact” of VIVA individual patient data analysis
The IPD analysis of the safety of paclitaxel-containing devices conducted by VIVA Physicians, based on the most complete available data set of mortality events from randomized controlled trials, identified an absolute 4.6% increased mortality risk—corresponding to a 38% increased relative mortality risk—associated with their use. This is a weaker mortality signal than that initially reported in December 2018 by Katsanos.
The analysis, based on the most complete available data set of mortality events from randomized controlled trials involving paclitaxel devices, included 2,185 patients (including those whose data were previously lost to follow-up) across eight studies, with a median follow-up of four years.
Presenting these results at CX 2020 LIVE, first published in Circulation, Gary Ansel, MD, of Columbus, Ohio, remarked: “The VIVA IPD has, and will continue to have, [a] high impact due to the richness of the dataset.”
Nearly two-thirds of the CX 2020 LIVE audience believe the VIVA Physicians’ IPD analysis does not provide consensus on the ongoing paclitaxel debate “once and for all.” When asked, “Does the VIVA IPD settle this once and for all?”, 63% answered “no.”
Greenhalgh concluded: “What we have learnt today, from various pieces of data, is that this matter is not settled. What I personally like is that the FDA’s comments have left room for doctors to decide what they consider to be the right thing to do for the patient.”
Recent meta-analyses have contradictory findings in patients with CLTI
Two analyses investigating the alleged increased rate of mortality with the use of paclitaxel-containing devices in the chronic limb-threatening ischemia (CLTI) population were presented back-to-back during the inaugural CX 2020 LIVE session.
Though Ramon Varcoe, MD, of Randwick, Australia, put forward that paclitaxel-coated devices were not associated with increased mortality in patients with CLTI, Katsanos told viewers that paclitaxel-coated balloons seemed to increase the risk of all-cause death, as well as the risk of amputation, in the infrapopliteal segment.
Expounding on the differences between the methodologies used by each research team, Varcoe said: “As I see it, there are four main differences. The first was [that] we had a different primary endpoint. We looked at all-cause mortality, and we did that because we were asking whether paclitaxel was associated with death; it makes sense to look at overall survival, rather than amputation-free survival, which is more of an efficacy endpoint.
“We also looked at paclitaxel use in stents and balloons above and below the knee, so we did not restrict it, and this was a way to replicate the original 2018 meta-analyses. But also, the rationale was if you are exposed to paclitaxel, it should not matter how it was used in the leg or what device.
“We also used only published data. As we know, data change between their presentation at symposium level and the subsequent peer review at publication, so we thought it was important to use locked and verified data in our analysis.
“Most importantly, we included the five-year data from the Medtronic IN.PACT DEEP study. This was the largest study in the meta-analysis, and the longest follow-up, and had the largest number of event rates in terms of mortality. It was the most influential in terms of a meta-analysis, and it really needed to be included, and that is what we did.”
The five-year findings of the IN.PACT DEEP study, which tested a 3.5μg/mm2 device, were not part of the Katsanos meta-analysis, a fact that garnered criticism from CX 2020 LIVE attendees. Justifying this choice to viewers, Katsanos said: “All the other studies have presented six-month to one-year data. It would not be very reasonable to combine that with the five-year data because then it becomes heavily skewed towards this study, as it a lot more events due to the five-year follow-up.”
Greenhalgh summarized: “I think we will accept that six-month data follow-up is limited.”
The discussion continues May 28
Session Two of CX 2020 LIVE will focus on the durability of EVAR, sac diameter and the UK National Institute for Health and Care Excellence (NICE) guidelines. To take part in the global conversation and participate in live polling, register here and join us from 4 p.m. to 5:20 p.m. BST on May 28. Roger Greenhalgh is returning as chair and Ian Loftus, MD, of London, will moderate the discussion.
