Medtronic and Cook Medical issue corrections to published data regarding the safety of their paclitaxelcovered devices Medtronic announce they have revised IN.PACT post-market study data due to a “programming error,” and Cook Medical note a mistake made during data publication: that two mortality figures were “inadvertently reversed”. According to Medtronic, mortality data were accidentally omitted from the summary tables included in the statistical analysis of their data presented at LINC. These deaths were, however, previously included and reported in Medtronic’s database, captured in the appropriate study exit forms and adjudicated by an independent clinical events committee. Immediately upon learning of this error, Medtronic notified the FDA and the study authors. The company stated that while a component of the recent patient-level meta-analysis will need to be updated, it has found the revised analysis still supports earlier conclusions. Cook Medical announce that in a paper published in Circulation in 2016 assessing the clinical effectiveness of their Zilver PTX stent, the mortality figures for the Zilver PTX arm and the PTA arm were swapped. Circulation state: “When high-resolution files were requested during production, an incorrect version of Figure 1 was mistakenly provided. Subsequently, the published version of the flow chart in Figure 1 contained incorrect numbers. The authors now provide the corrected version of Figure 1.”
Society for Cardiovascular Angiography and Interventions supports continued use of paclitaxel devices Experts from the Society for Cardiovascular Angiography and Interventions (SCAI) have reviewed the Katsanos et al publication and have concluded that the methods are appropriate and within constraints of trial-level metaanalysis. However, the society statement says “it is important to note that SCAI believes the associations are hypothesisgenerating and require further investigation with patient-level data.”
The last word
CX aims to give the last word The Charing Cross Symposium (CX; 15–18 April, London, UK) hosts a highlight session to independently review whether or not paclitaxel useage is beneficial or detrimental to the patient, and brings together the godfather of drugcoated balloons, Ulrich Speck, and Konstantinos Katsanos for the first time, with the aim of having the last word on this controversy.
The discussion continues at the Vascular Leaders Forum VIVA (Vascular Interventional Advances) assembles an invite-only special session of the Vascular Leaders Forum series on the topic “Drug elution in peripheral arterial disease (PAD): A critical analysis from a multidisciplinary consortium” (1–2 March, Washington, DC, USA). As reported on page 1 of this newspaper, the FDA announes during VLF that the regulatory body’s own preliminary evaluation confimed the mortality signal reported by Katsanos et al.
CRT panelists vote overwhelmingly for there being a mortality signal Polling of 14 panellists at CRT revealed that the majority of voters (10) believed there is “a mortality signal” in the metaanalysis. While none voted against, four responded that they “did not know” if there was a signal or not. In an additional poll, the panel voted eight to six not to change or restrict device labelling. Three voted to restrict and three voted to change labelling. The CRT panel voted unanimously to discuss the Katsanos et al meta-analysis findings with patients during conversations of informed consent. The final poll at CRT showed that the majority of the panel believed the industry patient-level data is poolable for definitive analysis. Nine voted for, one against, and four said they did not know.
Vast majority of ISET attendees will not change their use of paclitaxel devices following the Katsanos et al meta-analysis The 31st International Symposium on Endovascular Therapy (ISET; 27–30 January, Hollywood, USA) host a paclitaxel town hall to discuss the continued use of these devices. Following a morninglong discussion, 79% of the ISET audience do not believe the Katsanos et al findings are sufficient to change practice. Thirty-one percent of respondents said they would use paclitaxel devices less, while the remaining 69% answered that they would continue to use the devices as they always have. Several physicians voiced concerns regarding litigation following the FDA’s announcement that it is launching its own investigation.
29.01.19 BASIL-3 trial pauses for review of paclitaxel meta-analysis data The BASIL-3 trial pauses recruitment, stating there are concerns about patient safety following the outcomes of the JAHA meta-analysis.
Patient-level analysis presented at LINC from Medtronic, Cook Medical, and Philips reports no link between paclitaxel dose and mortality New data presented at the Leipzig Interventional Course (LINC) in Leipzig, Germany (22–25 January) by various industry leaders finds no association between paclitaxel dose and mortality. An independent, third party, pooled analysis of all the IN.PACT Admiral DCB (Medtronic) clinical programmes, published in the Journal of the American College of Cardiology and including 1,980 patients, demonstrated that at five years, there is no statistically significant difference in all-cause mortality between the DCB and the control arm (9.3% vs. 11.2% respectively, p=0.399). Ranger (Boston Scientific) SFA randomised trial three-year data from 105 patients showed no significant difference in all-cause mortality between DCB and control (13.8% vs. 10.7%, respectively). Results from a Cook Medical press release also demonstrated the safety of their drugeluting stent, the Zilver PTX. Patient-level data found no increased mortality at five years with Zilver PTX compared to non-coated stents and balloons (18.7% vs. 17.6% respectively, p=0.53). A pooled analysis of patient-level data from Philips also demonstrates the “strong safety profile” of the company’s Stellarex DCB in above-theknee studies, according to a company statement. The independent, third party pooled analysis evidenced low mortality rates through three years after the treatment with no device-related deaths. Fiveyear data from 1,189 patients in the Levant 2 trial within the Lutonix DCB (BD) programme showed no statistically significant difference in all-cause mortality between the DCB and the control group (14.2% vs. 10.6% respectively, p=0.22).
Medtronic and Boston Scientific stand by paclitaxel devices despite Katsanos’ critical study Speaking to investors at the JP Morgan healthcare conference in San Francisco, USA, executives from Medtronic and Boston Scientific said their data do not show the safety risks cited in Katsanos (Patras, Greece) et al’s published analysis. According to Star Tribune, the companies stated that they are not backing away from drug-eluting devices used in blood vessels in the legs, despite the conclusions of the JAHA meta-analysis. DCBs from both Medtronic and Boston Scientific (IN.PACT Admiral and Ranger, respectively) were used in the JAHA meta-analysis. Boston Scientific’s Eluvia drug-eluting stent also contains paclitaxel, though was not used in the analysis.
Without additional long-term and patientlevel data, Katsanos et al’s conclusion is premature In a commentary published by Interventional News, Thomas Zeller (Bad Krozingen, Germany) said: “I am concerned with the conclusion that there is an association between all-cause mortality and paclitaxel with no clear causal explanation of a pathophysiological mechanism of action. The authors spend no time exploring other potential hypotheses for the observed trends and the lack of patient-level data is a clear limitation to being able to draw these conclusions. As one of the investigators in several of the studies cited here—in particular of those with five-year follow-up (THUNDER, IN.PACT SFA randomised controlled trial, ZILVER PTX randomised controlled trial)—it is important to note that the observed trend is not new. In fact, we published two- and three-year results showing a statistically significant frequency of allcause mortality between DCB and plain balloon angioplasty (PTA) arms of the IN.PACT SFA study. We have subsequently presented on the four- and five-year data, showing no significant difference in mortality. Events in the trial were reviewed by an independent clinical events committee and none were related to the device, or paclitaxel.”
SWEDEPAD 1 and SWEDEPAD 2 trials halt inclusion Inclusion into the SWEDEPAD studies, examining the benefits of drug-eluting technology for peripheral arterial disease (PAD) patients, has been halted. As outlined in the public domain, the SWEDEPAD (Swedish drug-elution trial in PAD) project is designed to test the hypothesis that drug-eluting technology is superior to conventional endovascular treatment in terms of important clinical outcomes, when applied on infrainguinal (femoropopliteal and/or infrapopliteal) obstructive vascular lesions. The SWEDEPAD project consists of two separate parallel studies, SWEDEPAD 1 and SWEDEPAD 2, each defined by the severity of PAD. As noted on clinicaltrials.gov, “patients with critical limb ischaemia are allocated to SWEDEPAD 1 and patients with intermittent claudication are allocated to SWEDEPAD 2.” The trials had a planned enrolment of 3,800 participants. An update on the SWEDEPAD website (when translated into English) reads: “Inclusion in SWEDEPAD studies stop! On the occasion of the Katsano’s [sic] systematic literature review published today, the study management has today met with the Data Safety Monitoring Committee (DSMC) in SWEDEPAD. After DSMC performed an interim safety analysis of the study’s prespecified and monitored safety variables (occlusion rate, amputation rate and mortality by 30 days and one year) distributed on treatment allocation, the recommendation from DSMC is to promptly pause further inclusion in both SWEDEPAD 1 and SWEDEPAD 2.”
The US FDA evaluates paclitaxel data, and recommends patient surveillance The US Food and Drug Administration (FDA) begins to evaluate its recommendations for the treatment. In a letter to healthcare providers, the FDA states that it is evaluating the “recent information regarding the potential for increased long-term mortality” following paclitaxel-coated balloon or paclitaxel-eluting stent treatments in the femoropopliteal artery for patients with PAD. Whilst the data review is ongoing, the regulatory body recommends “continued surveillance” for patients treated with paclitaxel. The FDA believes the “benefits continue to outweigh the risks” for approved devices used within their indications.
Paclitaxel-releasing devices: An unfolding story Meta-analysis finds a higher risk of death in the long term when paclitaxel-coated devices are used in the leg Konstantinos Katsanos (Patras, Greece) and colleagues publish data in the Journal of the American Heart Association (JAHA) suggesting that there is an increased risk of death at two and five years following the use of paclitaxel-releasing balloons and stents in the femoropopliteal artery. The investigators conducted a systematic review and metaanalysis of 28 randomised controlled trials with a total of 4,663 patients investigating paclitaxelcoated balloon angioplasty or paclitaxel-coated metal stents in arteries in the leg. At one year, all-cause patient death was similar between 17 paclitaxel-coated devices and control arms (2.3% vs. 2.3% crude risk of death). All-cause death at two years was significantly increased in the case of paclitaxel versus control (7.2% [101 deaths in 1,397 patients] vs. 3.8% [35 deaths in 919 patients] crude risk of death, number-needed-to-harm [NNH]: 29 patients [95% CI: 19–59]). Long-term risk of all-cause death up to five years increased further in the case of paclitaxel (14.7% [78 deaths out in 529 patients] versus 8.1% [27 deaths in 334 patients] crude risk of death, NNH: 14 patients [95% CI: 9–32]). While the authors write that their findings are supported by robust statistical evidence, some leading physicians state that it lacks individual patient-level data from the randomised controlled trials. Katsanos and colleagues end their paper by saying that “further investigations are urgently warranted”. See page 51 for a BIBA MedTech survey capturing the physician response.