Abstract: Background. A meta-analysis of trials in endovascular therapy suggested an increased mortality associated with treatment exposure to paclitaxel. Multiple publications and corrections of prior data were performed, and the United States Food and Drug Administration has issued multiple advisories regarding paclitaxel use. We analyzed how this controversy impacted device purchasing and related utilization patterns in the period immediately following publication of the meta-analysis. Methods and Results. Ascension Healthcare System purchase data over a 14-month period were synthesized across centers for both paclitaxel and non-paclitaxel devices. A fixed-effects regression model and a binary regression model with facility-level controls were used to compare purchasing patterns before and after the meta-analysis. Purchase volumes of each paclitaxel device fell. Pooled purchase volumes of all paclitaxel devices decreased from a 14-month peak of 631 devices in October 2018 to a 14-month nadir of 359 devices in February 2019. An F-test comparing the pooled-month specific fixed effects for the months before vs after the publication of the meta-analysis has an F-statistic of 11.64, suggesting that average purchasing levels in the two periods are statistically different (P<.001). Utilization of non-paclitaxel devices did not decline. Conclusions. Purchase volumes of paclitaxel devices decreased immediately during the months following publication of the related meta-analysis. Total Ascension-wide paclitaxel device purchase volume in February 2019 demonstrated a 43.1% reduction from peak monthly purchase volume during the assessed period and a 32.5% reduction compared with November 2019, the last month preceding publication of the meta-analysis.
J INVASIVE CARDIOL 2020;32(1):18-24. Epub 2019 October 15.
Key words: critical limb ischemia, peripheral vascular disease, restenosis, revascularization, stenosis, stent
Peripheral artery disease (PAD) of the lower extremities affects 200 million people globally, with a projected continued rise in incidence given the increasing burden of risk factors and an aging population.1-3 Endovascular therapies for PAD have evolved continuously, providing improving rates of success for the treatment of increasingly complex disease. Initially, angioplasty alone was available for vessel recanalization. Over time, novel stenting technologies developed with a primary goal of improving rates of target-lesion revascularization (TLR).
Femoropopliteal interventions comprise the majority of lower-extremity endovascular procedures. When utilized in the femoropopliteal arteries, traditional peripheral stent technologies often improved TLR compared with percutaneous transluminal angioplasty (PTA) alone, but continued to be plagued by significant rates of in-stent restenosis, compressive mechanical failure, and TLR.4-6 Drug-coated balloons (DCBs) and drug-eluting stents (DESs) impregnated with an antiproliferative agent, specifically paclitaxel, were developed with hopes of continuing to decrease TLR rates.
Paclitaxel has been studied extensively with in vivo and in vitro models. Due to its unique lipophilic properties, high degree of intimal uptake, and lasting local effects, it is considered an ideal agent for local treatment to prevent neointimal hyperplasia.7-9 Industry-sponsored clinical trials utilizing paclitaxel DES and DCB devices for PAD demonstrated improved primary patency rates and freedom from clinically driven TLR when compared with traditional stent technologies. Long-term paclitaxel device analysis continued to demonstrate this trend 3-5 years after intervention.10-12 As a result, the Society for Cardiovascular Angiography and Interventions (SCAI) consensus guidelines for device selection in femoropopliteal arterial interventions published in March 2018 list several class I indications for drug-coated devices as potential definitive therapies.13
On December 6, 2018, a meta-analysis of 28 randomized controlled trials using DES and DCB devices in femoropopliteal endovascular intervention was published by Katsanos et al.14 It reported a previously undocumented increase in mortality associated with treatment exposure to paclitaxel. All-cause death up to 5 years after intervention was increased with paclitaxel exposure (14.7% vs 8.1%; risk ratio, 1.93; 95% confidence interval, 1.27-2.93).14 Preceding publication of this work, individual paclitaxel device studies had not reported this signal. Katsanos’s work prompted reevaluation of individual study data that has since unearthed relevant discrepancies regarding previously reported mortality data beyond 2 years.
In December 2018, in direct response to this report, two major international randomized controlled trials (BASIL-315 and SWEDEPAD16) abruptly halted ongoing patient recruitment secondary to concerns of including paclitaxel-based therapies. As concerns continued to mount, Ascension Healthcare instituted a “voluntary moratorium” on paclitaxel-containing devices for PAD on January 11, 2019. Only days later, on January 17, 2019, the U.S. Food and Drug Administration (FDA) issued a “dear doctor” letter that concluded with the following language: “the FDA believes that the benefits continue to outweigh the risks for approved paclitaxel-coated balloons and paclitaxel-eluting stents when used in accordance with their indications for use.”17 As a result, on January 22, 2019, Ascension lifted the paclitaxel moratorium after 11 days.
On January 22-25, 2019, extensive industry data were presented at the Leipzig Interventional Course (LINC) reporting the safety of paclitaxel devices. On January 25, 2019, Schneider et al presented an independent meta-analysis demonstrating no increased mortality with paclitaxel therapies.18 Concerns were further alleviated on February 12, 2019, when Secemsky et al reported Medicare outcomes data demonstrating no mortality increase with paclitaxel therapies.19 On February 18, 2019, Medtronic issued a statement to report that a software issue caused an error in mortality reporting within the In.Pact global postmarket registry.20 A day later on February 19, 2019, a correction was issued in Circulation stating that the initial 2016 publication of the Zilver PTX 5-year data had “inadvertently reversed” the mortality rates for the primary PTA and DES groups.21 At this point, concern enveloped all paclitaxel-delivering (DES and DCB) devices.
Then, on March 15, 2019, the FDA issued an update to its prior advisory stating that its own “preliminary” analysis had identified a 50% higher relative risk of death among patients with femoropopliteal artery disease who received paclitaxel-coated devices vs control devices.22 The advisory recommended that clinicians “consider that there may be an increased rate of long-term mortality in patients treated with paclitaxel-coated balloons and paclitaxel-eluting stents” and seems to recommend that paclitaxel devices “should be reserved for those at particularly high risk of restenosis.” It further states that “for most patients, alternative treatment options to paclitaxel-coated balloons and paclitaxel-eluting stents should generally be used until additional analysis of the safety signal has been performed”22 (Figure 1).
The addition of paclitaxel to angioplasty and stent devices was intended to improve freedom from repeat intervention after treatments often aimed at improving pain-free ambulation (as well as treatment of critical limb ischemia).The Katsanos meta-analysis14 raised concerns that paclitaxel utilization was associated with an increased risk of mortality. In the months following publication of this analysis, uncertainty placed a unique burden on healthcare systems and individual practitioners as important decisions were made in real time regarding the utilization of paclitaxel devices for patient care.
Ascension Healthcare system is the nation’s largest nonprofit hospital system, encompassing 151 hospitals in 21 states and the District of Columbia. The Ascension Healthcare system includes sites ranging from outpatient clinics to quaternary-care referral centers. Both teaching hospitals and private facilities of all sizes are represented. The system is thus broadly representative of healthcare practices across the United States. Ascension utilizes a large group-purchasing organization to leverage the collective purchasing power of the entire system to optimize procurement and costs of devices and equipment utilized in medical procedures and services. The Resource Group is a large resource and supply management organization that functions as the purchasing organization for Ascension Healthcare. All device contracting for Ascension sites is performed centrally; thus, any device available at one Ascension facility is available at all Ascension facilities, and all costs associated with a given device are equivalent across all sites. All purchasing data across the network are reliably monitored centrally and in real time.
Clinical oversight of cardiac device purchasing decisions, contract development, and clinical initiatives is guided by the Ascension Cardiovascular Service Line. The Ascension Cardiovascular Service Line is composed of leaders from Ascension sites across the country and its goal is to align the physicians, staff, and leadership to make collaborative, unified decisions governing cardiovascular strategy and implementation. One division of the Service Line is the Peripheral Vascular Affinity Group, whose goal is to guide systems initiatives, clinical strategy, and contract and purchase decisions for peripheral vascular devices. The Peripheral Vascular Affinity Group is also responsible for outreach to the Ascension clinician community regarding changes in device availability, as well as to issue warnings and concerns regarding devices available on Ascension’s contract.
Each Ascension site is independently responsible for purchase-volume decisions of cardiovascular devices available on contract by Ascension Healthcare. All Ascension sites purchase based on a “use and replace” model. By this model, the frequency and volume of device purchases are driven by the volume of device use in the preceding period. Clinical demand for devices is also incorporated to determine forward purchase volume.
Purchasing data were obtained for each of the 3 paclitaxel-coated DCB devices available on Ascension contract (Bard Lutonix, Medtronic In.Pact Admiral, and Spectranetics Stellarex). Purchasing data for the sole self-expanding DES available on Ascension contract (Cook Zilver PTX) were also obtained. Purchasing data were also obtained for the most commonly utilized peripheral atherectomy devices (Cardiovascular Systems Diamondback 360 peripheral orbital atherectomy, Medtronic HawkOne, and Boston Scientific Jetstream), as were purchasing data for all non-drug coated self-expanding stents (Abbott, BD, Boston Scientific, Cardinal, Cook, Medtronic, Merit, and Gore).The Cook Ansel and Raabe sheaths were the most frequently utilized sheaths within Ascension facilities for peripheral interventions and purchasing data were obtained for all Cook Ansel and Raabe sheaths during the same period.
The reported volumes are purchasing volumes for the entire healthcare system; thus, they represent purchase volumes for use by all subspecialties performing peripheral vascular procedures within Ascension facilities. Raw purchasing data, including direct unit purchase quantities, are presented by month. Where trendlines are presented, moving averages are utilized with a period of 2 months. We estimated two types of linear-regression models to assess whether the apparent downward trends were statistically significant in the months following the publication of the negative meta-analysis. To do so, we estimated a parsimonious fixed-effects model and a simple binary linear regression, predicting purchase orders using hospital fixed effects and either month-level fixed effects or a binary indicator of whether or not the month of observation was before or after the publication of the meta-analysis. Both models included facility-level controls. After estimating the model with monthly fixed effects, we conducted an F-test comparing the average month-specific fixed effect for the months before and after the meta-analysis was published. Next, in a simple binary linear-regression model, we estimated the coefficient on a binary indicator for months observed in the period post meta-analysis. This provided an estimate of the monthly decrease in orders in paclitaxel devices at the hospital level for which we could also test the significance of the decline. While this binary indicator model includes more statistical modeling assumptions, it also yields a parameter estimate that is more easily interpretable, ie, the average decline in monthly orders across all hospitals.
Raw data regarding device purchase volume across Ascension Healthcare were obtained on a monthly basis over the 14-month period from January 1, 2018 through February 28, 2019. Individual sites purchased devices as infrequently as 1 time (low-volume use sites) and as frequently as (at least) 14 times over the 14-month period. Because purchase volumes were obtained at a monthly interval, the product volumes of sites that purchased more frequently than once monthly were aggregated to the calendar month in which purchases occurred. During the period of observation, DCB purchases occurred at between 40 and 49 sites per month (mean, 45.3 ± 2.5 sites). The largest number of hospitals purchasing DCBs in a given month occurred in April 2018 (n = 49), with the fewest hospitals (n = 40) purchasing DCBs in February 2019. DES purchases occurred at between 10 and 18 sites per month (mean, 14.6 ± 2.1 sites), with a peak in May 2018 (n = 18) and with the fewest hospitals (n = 10) purchasing DES devices in December 2018.
Total purchase volumes of the 3 DCB devices available on Ascension contract are presented in Figure 2A (Medtronic, Spectranetics, Bard). Pooled volumes of DCB purchases by month are presented in Figure 2B.Total DCB purchase volume peaked in October 2018 (547 DCBs purchased) and reached its nadir in February 2019 (307 DCBs purchased). Total purchase volumes of the single DES device available on Ascension contract (Cook Zilver PTX) are presented in Figure 2C. Over the period of observation, total DES purchase volume peaked in October 2018 (84 DES devices purchased) and reached its nadir in February 2018 (43 DES devices purchased).
Figure 2D presents the total purchase volume by month of all paclitaxel devices across the Ascension Healthcare network. Total paclitaxel device purchase volume peaked in October 2018 (631 devices purchased) and reached its nadir in February 2019 (359 paclitaxel devices purchased). In November 2018, the last month preceding publication of the Katsanos meta-analysis, a total of 532 paclitaxel devices were purchased. Thus, total Ascension-wide paclitaxel device purchase volume in February 2019 demonstrated a 43.1% reduction from peak monthly purchase volume during the assessed period and a 32.5% reduction compared with November 2019, the last month preceding publication of the meta-analysis. Of note, as demonstrated in Figures 2B and 2D, a decrease occurred in purchase volumes from October 2018 to November 2018. However, the October 2018 peak was likely compensatory for a relatively low purchase volume in September 2018. Indeed, the November 2018 purchase volume (although lower than the October 2018 purchase volume) was similar to purchase volumes between February and August 2018.
Comparisons were made between purchase volumes made exclusively in February 2018 and those made exclusively in February 2019 across individual sites purchasing paclitaxel devices. A total of 46 distinct sites purchased paclitaxel devices (DCB or DES) in February 2018 and 41 distinct sites purchased paclitaxel devices in February 2019. Of the sites that purchased paclitaxel devices in February 2018, a total of 29 sites (63%) purchased a smaller total volume of paclitaxel devices in February 2019 than they had purchased in February 2018. Three sites (6%) purchased the same total volume of paclitaxel devices in February 2018 as in February 2019, and 14 of these sites (30%) purchased a larger total volume of paclitaxel devices in February 2019 than in February 2018. Of note, two sites purchased paclitaxel devices in February 2019, but not in February 2018. Among the sites purchasing paclitaxel devices, the average purchase volume was 11 ± 12.0 devices in February 2018 and 9 ± 7.3 devices in February 2019.
To better evaluate whether trends in paclitaxel device purchasing impacted trends in purchasing of other peripheral vascular equipment purchasing volumes, total purchase volumes of the 3 most frequently used peripheral atherectomy devices were obtained (Figures 3A and 3B), as well as total purchase volumes of the 8 most frequently utilized non-paclitaxel self-expanding stents (Figures 3C and 3D).
To further determine if trends in paclitaxel device purchasing were representative solely of decreased performance of peripheral vascular procedures in general, total purchase volumes of the most commonly used peripheral sheaths at Ascension Healthcare sites for femoropopliteal peripheral interventions (Cook Ansel and Cook Raabe) were identified (Figure 4A). Other sheaths are utilized for peripheral procedures and therefore this reported sheath volume is meant not to represent a “total peripheral procedure number,” but rather to represent a stable index representative of purchasing volume for peripheral vascular procedures. Total paclitaxel device purchase volume indexed to selected peripheral sheath purchase volume is presented in Figure 4B. Of note, with indexed purchase volumes, the decrease in raw purchase of paclitaxel devices that was demonstrated to occur in Figure 2D to begin after October 2018 now clearly demonstrates a decrease only after December 2018, which correlates directly with publication of the Katsanos meta-analysis. Also presented in Figure 4B is the total non-paclitaxel self-expanding stent purchase volume indexed to sheath purchase volume. This indexed value for non-paclitaxel self-expanding stents demonstrates no significant variation over the reported period, including following publication of the meta-analysis.
Also of note, whereas raw purchase volumes of all devices (paclitaxel devices, atherectomy devices, non-paclitaxel self-expanding stents, sheaths) dropped acutely in September 2018 and then rose in October 2018 (both preceding the meta-analysis), the purchase volumes of both paclitaxel devices and non-paclitaxel self-expanding stents indexed to sheath purchases remained stable during this period (Figure 4B).
In order to assess the statistical significance of the downward trends in paclitaxel device purchasing and indexed paclitaxel device purchasing in Figures 2 and 4B, we report results from fixed-effects and binary-regression models. An F-test comparing the pooled month-specific fixed effects for the months before vs after the publication of the meta-analysis has an F-statistic of 11.64, suggesting that average purchasing levels in the two periods are statistically different (P<.001). The regression model using a binary indicator estimates that after accounting for facility-specific factors, the post-meta-analysis period was associated with an average decline in monthly purchases at a hospital level of 2.83 paclitaxel devices (24.3% of the pre-meta-analysis monthly average of 11.64 devices).
As physicians, our absolute priority is to do no harm. As vascular interventionalists, we often tackle claudication with procedural revascularization not to save a limb or to save a life, but rather to improve a patient’s quality of life. When we are forced to question whether an intervention aimed at improving quality of life may in fact pose a significant risk of long-term patient harm, device implementation patterns will change. The FDA did not prohibit national use of paclitaxel within their updated letter, but rather recommended that “for some individual patients at particularly high risk for restenosis, clinicians may determine that the benefits of using a paclitaxel-coated product may outweigh the risks.”22 Our data demonstrate for the first time the magnitude of the dramatic and immediate impact of this ongoing controversy on purchasing and use patterns of paclitaxel in a large national healthcare system broadly representative of national use.
Although we do not observe direct utilization of paclitaxel devices, the “use and replace” purchasing model employed by Ascension Healthcare implies a direct — but perhaps lagged — correlation between device purchasing and device utilization. Furthermore, trends in purchasing may represent an equally important metric regarding the impact of the paclitaxel controversy in clinical research on clinical practice within healthcare systems.
We utilized the purchase volume of the most commonly used sheaths for peripheral procedures within the system to further assess the purchase pattern of paclitaxel devices. Of note, this purchase volume of the most common sheaths is not directly representative of the total number of peripheral procedures performed. Other long sheaths, as well as short sheaths (for antegrade access, etc), are used often for both peripheral and non-peripheral procedures. Rather, the assessed sheath volumes are utilized to supply a stable index representative of purchasing volumes for peripheral vascular procedures in general. Indexing paclitaxel device purchasing to the purchasing of the most commonly used sheaths within the same healthcare system demonstrates that the post-meta-analysis trends in paclitaxel purchasing are not representative of a decrease in peripheral interventions in general, but rather appear to be representative of an isolated decrease in purchases of paclitaxel devices specifically. In fact, indexing to sheath purchasing also reveals the pronounced decrease in purchasing of paclitaxel devices immediately after publication of the meta-analysis. Furthermore, when purchases of non-paclitaxel self-expanding stents are indexed to this same sheath purchase metric, a stable indexed purchasing of non-paclitaxel self-expanding stents is demonstrated.
A decrease in purchasing of all device purchasing assessed was demonstrated in September 2018, followed by an increase in purchasing in October 2018. Indexing of both paclitaxel device purchase volume and non-paclitaxel self-expanding stent volume to sheath purchase volume made clear that these September-October 2018 fluctuations were consistent across devices when indexed to the purchasing of a device (sheaths), which should not have fluctuated regardless of type of procedure performed and regardless of a given device incorporating paclitaxel. It thus appears that the September-October 2018 purchase volume changes were secondary to a general trend in device purchasing rather than a selective purchasing trend driven by considerations regarding paclitaxel’s presence or absence within a device.
The statistically significant decrease in direct purchasing of paclitaxel devices immediately after meta-analysis publication demonstrates that the uncertainty in the emergent clinical research regarding the relationship between paclitaxel utilization and mortality rapidly impacted decision making of clinicians in the Ascension Healthcare system, a set of facilities that is broadly representative of national practice patterns.
Looking ahead, it will be interesting to see both how this trend evolves and to see if any lagged trends emerge in the utilization of other devices – for example, will we see increased use of non-paclitaxel self-expanding stents? Or might we observe decreased use of atherectomy (which is potentially more necessary for adequate vessel preparation if DCB is used and thus no stent scaffold is placed)?
It is important to note that not all atherectomy devices or self-expanding stents are captured in the data presented here. Rather, the most frequently used devices of this type are represented for purposes of presenting broad trends. It is also important to note that the newly released Boston Scientific Eluvia paclitaxel-coated stent is not included in this analysis, as this stent is not available on contract through Ascension Healthcare and thus is not utilized at Ascension clinical sites.
Though limited, the site-specific analysis comparing February 2018 and February 2019 demonstrates that matched for time of year, fewer sites purchased paclitaxel devices in February 2019 versus February 2018, and the sites that did purchase paclitaxel devices exhibited a trend toward purchasing fewer devices in February 2019 versus February 2018. It is important to note that a large standard deviation in site-level purchasing makes this result far from statistically significant and month-to-month variation in site purchasing frequency makes this measurement susceptible to random error. This February 2018 versus February 2019 analysis is presented to demonstrate that the trending decrease in purchases since October 2019 is likely not solely representative of fluctuating annual cycles in purchase patterns. It is also important to note that even if the short 28-day month of February is “corrected” to a 30-day month, it would still represent the nadir of paclitaxel device purchase volume over the period of observation (359 x 30/28 = 384 devices).
The Ascension Healthcare system has developed processes that facilitate a rapid response to new clinical data as they become available. Within months of concerns being raised about associations between paclitaxel and increased mortality, purchasing of paclitaxel devices decreased significantly across the network. The Ascension Cardiovascular Service Line and its Peripheral Vascular Affinity Group distributed real-time information to its providers regarding concerns raised in the literature about paclitaxel, supplementing Ascension clinician awareness. Although changes in paclitaxel utilization of note would impact cost and reimbursement to the healthcare system, it is important to note that communications from the Peripheral Vascular Affinity Group during the assessed period were solely focused on clinical and not economic concerns of paclitaxel utilization. The uncertainty in the medical literature had a meaningful impact on purchasing and thus utilization in Ascension hospitals.
We as a community remain confident that paclitaxel decreases TLR. Yet, we have seen extreme variations in reports of the safety of paclitaxel with regard to increasing mortality risk. We thus eagerly await continued complete and transparent reporting of clinical data so we can direct and formulate our future strategies to provide safe, effective, and informed patient-centered care.
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From 1Ascension Healthcare, St. Louis, Missouri; 2The University of Texas at Austin Dell School of Medicine, Seton Heart Institute, Austin, Texas; 3VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas, Texas; 4Harvard Business School and Harvard-MIT Center for Regulatory Science, Boston, Massachusetts; 5University of Southern California, Marshall School of Business, Department of Management & Organization, Los Angeles, California; 6Orbimed Advisors, New York, New York; and 7Saint Vincent’s Heart Center, Indianapolis, Indiana.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Monteleone reports consulting income and an institutional research grant from Medtronic for work unrelated to this project; non-compensated research data-sharing agreement with Abbott Vascular. Dr Banerjee reports honoraria from Medtronic and AstraZeneca; institutional research grants from Boston Scientific, Abbott Vascular, and Chiesi.Dr Fry reports equity ownership in Abbott Vascular, Johnson & Johnson, and the Care Group Heart Hospital. Drs Monteleone, Fry, and Pirwitz are employees of Ascension Medical Group. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 24, 2019, provisional acceptance given July 5, 2019, final version accepted September 9, 2019.
Address for correspondence: Peter Monteleone, MD, Seton Heart Institute, The University of Texas at Austin Dell School of Medicine, 1301 West 38th Street, Suite 400, Austin, TX 78701. Email: firstname.lastname@example.org