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approved device, so an institutional review board/ethics committee

approval was not required.

References

1. Madhavan MV, Tarigopula M, Mintz GS, Maehara A, Stone GW, Genereux P.

Coronary artery calciﬁcation: pathogenesis and prognostic implications. J Am Coll

Cardiol. 2014;63(17):1703–1714.

2. Kobayashi Y, Okura H, Kume T, et al. Impact of target lesion coronary calciﬁcation on

stent expansion. Circ J . 2014;78(9):2209–2214.

3. Mintz GS. Intravascular imaging of coronary calciﬁcation and its clinical implications.

J Am Coll Cardiol Img. 2015;8(4):461–471.

4. Chambers JW, Feldman RL, Himmelstein SI , et al. Pivotal trial to evaluate the

safety and efﬁcacy of the orbital atherectomy sy stem in treating de novo,

severely calciﬁed coronary lesions (ORBIT II). J Am Coll Cardiol Intv. 2014;7(5):

510–518.

5. Abdel-Wahab M, Toelg R, Byrne RA, et al. High-speed rotational atherectomy versus

modiﬁed balloons prior to drug-eluting stent implantation in severely calciﬁed

coronary lesions. Circ Cardiovasc Interv. 2018;11(10):e007415.

6. Kereiakes DJ, Virmani R, Hokama JY, et al. Principles of intravascular lithotripsy for

calciﬁc plaque modiﬁcation. J Am Coll Cardiol Intv. 2021;14(12):1275–1292.

7. Hill JM, Kereiakes DJ, Shlofmitz RA, et al. Intravascular lithotripsy for treatment of

severely calciﬁed coronary artery disease. J Am Coll Cardiol. 2020;76(22):

2635–2646.

8. Tepe G, Brodmann M, Werner M, et al. Intravascular lithotripsy for peripheral artery

calciﬁcation: 30-day outcomes from the randomized disrupt PAD III trial. J Am Coll

Cardiol Intv. 2021;14(12):1352–1361.

9. Kereiakes DJ, Di Mario C, Riley RF, et al. Intravascular lithotripsy for treatment of

calciﬁed coronary lesions: patient-level pooled analysis of the disrupt CAD studies.

J Am Coll Cardiol Intv. 2021;14(12):1337–1348.

J.D. Corl et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100969 5

Original Research

Five-Year Independent Patient-Level Mortality Analysis of the Pooled

ILLUMENATE Pivotal and EU Randomized Controlled Trials

Sean P. Lyden, MD

, Marianne Brodmann, MD

, Henrik Schroeder, MD

Andrew Holden, MD

, Kenneth Ouriel, MD, MBA

, Trisha R. Tarra, PhD

William A. Gray, MD

Department of Vascular Surgery, Cleveland Clinic, Cleveland, Ohio;

Division of Angiology, Medical University Graz, Austria;

Center for Diagnostic

Radiology and Minimally Invasive Therapy, The Jewish Hospital, Berlin, Germany;

Auckland City Hospital, Auckland, New Zealand;

NAMSA, New York,

New York;

Philips North America LLC, Cambridge, Massachusetts;

Lankenau Heart Institute/Main Line Health, Wynnewood, Pennsylvania

ABSTRACT

Background: There is a need to evaluate the latest information regarding a potential late safety signal in patients treated with paclitaxel-coated devices for

peripheral artery disease. We evaluated the 5-year all-cause mortality rate of the Stellarex drug-coated balloon (DCB) compared with percutaneous

transluminal angioplasty (PTA).

Methods: An independent third-party performed a patient-level meta-analysis of the pooled ILLUMENATE Pivotal and EU randomized controlled trials. The

primaryoutcome was time to death. Kaplan-Meierestimatesof all-cause mortality were compared with thelog-rank test. Predictors of mortality were assessed with

Cox proportional hazard modeling. A blinded clinical events committee adjudicated all serious adverse events (including death). The follow-up was 60 months.

Results: A total of 589 patients were followed for a median of 4.9 years (IQR, 4.8, 5.1 years); 419 were randomized to Stellarex DCB and 170 to PTA. Vital

status was obtained for 93.8%. The 5-year Kaplan-Meier estimates of freedom from all-cause death were 80.4% (95% CI, 76.7%-84.3%) in the Stellarex DCB

arm versus 80.4% (95% CI, 74.3%-86.5%) in the PTA arm (log-rank, P ¼ .7754). There was no difference in all-cause mortality when stratiﬁed by paclitaxel dose

terciles. Predictors of mortality included renal insufﬁciency, reference vessel diameter, age, and lesion length, but not paclitaxel dose nor paclitaxel exposure.

Conclusions: There was no difference in all-cause mortality between the Stellarex DCB and PTA through the ﬁnal 5-year follow-up window of 2 ILLUMENATE

randomized controlled trials. These long-term data build on the previously reported safety of the Stellarex DCB for treating symptomatic femoropopliteal

peripheral artery disease.

Introduction

Peripheral artery disease (PAD) affects 230 million people worldwide

and is associated with an increased risk of cardiovascular events and a

crude mortality rate of 33.2% at 5 years.

1,2

In patients with symptoms

that persist despite optimal medical therapy and lifestyle modiﬁcations,

minimally invasive treatment modalities such as percutaneous trans-

luminal therapy (PTA)are often preferred over open surgical options but

remain limited by high rates of restenosis at 1 year.

The advancement

of drug-coated balloons (DCBs) containing the antiproliferative drug

paclitaxel has consistently shown improved patency and reduced

clinically driven-target lesion revascularization (CD-TLR) compared with

standard PTA.

4–7

Despite demonstrating superior efﬁcacy, a 2018 sys-

tematic review and summary-level meta-analysis performed by Katsanos

et al of 28 randomized controlled trials (RCTs) suggested an increased

late-term mortality risk in patients treated with paclitaxel-coated devices

relative to uncoated devices.

Limitations of the Katsanos meta-analysis

included a lack of ho-

mogenous, patient-level data and the absence of a mechanism to

explain the late mortality signal. Furthermore, because of limited pa-

tient follow-up available, the mortality risk was derived from just 12

studies at 2 years and 3 studies at 5 years, totaling 679 patients.

Abbreviations: CEC, clinical events committee; DCB, drug-coated balloon; PAD, peripheral artery disease; PTA, percutaneous transluminal angioplasty; RCT, randomized

controlled trial.

Keywords: drug-coated balloon; meta-analysis; mortality; paclitaxel; peripheral artery disease.

Previously presented at Charing Cross (Virtual) on April 19, 2021. ISET in Miami Beach, Florida, on May 11, 2021. NCVH in New Orleans, Louisiana, on June 2, 2021. AMP in

Orlando, Florida, on August 12, 2021. ISET in Hollywood, Florida, on January 17, 2022, and NCVH in New Orleans, Louisiana, on June 1, 2022.

* Corresponding author: grayw@mlhs.org (W.A. Gray).

https://doi.org/10.1016/j.jscai.2023.100634

Received 3 January 2023; Received in revised form 3 March 2023; Accepted 11 March 2023

the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100634

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Following a Food and Drug Administration (FDA) advisory meeting in

June 2019, it was determined that there was insufﬁcient data to make a

ﬁnal decision regarding paclitaxel-coated device safety, and more

complete long-term follow-up data were needed.

A third-party meta-analysis of the 2 ILLUMENATE RCTs performed in

2019 using patient-level data showed there was no difference in all-

cause mortality through 3 years between the Stellarex DCB (Philips

North America) and PTA.

A 4-year meta-analysis following the same

methodology also showed no difference in all-cause mortality.

The

ﬁnal 5-year follow-up mortality analysis of the Stellarex DCB of the

ILLUMENATE RCTs has been eagerly anticipated by the FDA and in-

dustry alike.

The current meta-analysis aims to assess all-cause mortality through

the 5-year follow-up window of the ILLUMENATE Pivotal and EU RCTs.

Materials and methods

Data sources

The full data sources, study device and procedure, outcomes, and

statistical analyses were published previously.

Brieﬂy, the study pop-

ulation was pooled from the ILLUMENATE Pivotal (NCT01858428) and

ILLUMENATE EU (NCT01858363) RCTs. Both RCTs were prospective,

randomized, multicenter, single-blinded studies. Patients with Ruth-

erford 2-4 femoropopliteal disease were randomized 2:1 (Pivotal) or

3:1 (EU) to receive treatment with either the Stellarex DCB or PTA.

Because of the differences in device design, operators were not able to

be blinded to the actual devices. Follow-up was through 5 years

post-procedure and was performed during ofﬁce visits at 1, 2, and 3

years and via telephone contact at 4 and 5 years.

Inclusion and exclusion criteria were published previously.

Of note,

patients who had received prior treatment of the target lesion with a

paclitaxel-coated device at any time (EU RCT) or within 6 months

(Pivotal RCT) were excluded from the study. In addition, in the Pivotal

RCT only, patients were also excluded if they had received prior treat-

ment of the contralateral limb with the Stellarex DCB.

Study protocols were approved by either an independent review

board or ethics committee at each site and the study was conducted in

accordance with the Declaration of Helsinki. All patients provided

written consent. Adverse events were monitored at each site for data

accuracy and completeness and were adjudicated by an independent

clinical events committee (CEC). The study sponsor (Philips North

America) oversaw study design and data collection, and an indepen-

dent third-party, Syntactx, performed all analyses.

To account for differences between the 2 RCTs, variable names and

units were harmonized, and the data sets were merged using R software

version 3.5.2 (R Foundation for Statistical Computing).

Study device and procedure

Patients were treated with either PTA or the 0.035” over-the-wire

Stellarex DCB. The Stellarex DCB consists of a polyethylene glycol

excipient and a hybrid combination of amorphous and crystalline

paclitaxel (2 ug/mm

Outcomes

The outcome was time to death over 60 months postindex pro-

cedure and was assessed in the vital status cohort, which was comprised

of the intent-to-treat population as well as patients who had exited the

study but whose vital status was retrospectively obtained. If patients did

not reach the end point by the end of the 5-year follow-up period, they

were censored at their last day of contact or at 5 years (whichever

occurred ﬁrst). A safety ofﬁcer classiﬁed causes of death according to

the Medical Dictionary for Regulatory Activities version 21.0 System of

Organ Class. Deaths were recorded as cardiovascular- or

noncardiovascular-related, and deﬁnitions for each were described

previously.

Any undetermined cause of death was classiﬁed as

noncardiovascular.

Paclitaxel dose analyses

In patients treated with the Stellarex DCB, the nominal dose of

paclitaxel was stratiﬁed into terciles and compared with PTA to assess

the relationship between exposure to the drug and all-cause mortality.

The mean nominal dosages were classiﬁed as no paclitaxel (0 mg) in the

PTA arm and low (0.1-3.2 mg), medium (3.3-5.2 mg), or high (5.3 mg)

paclitaxel doses in the Stellarex DCB arm. The size of the balloon

(surface area [diameter and length]) and the number of devices used

during treatment were used to determine the maximum potential

paclitaxel dose.

Statistical analysis

The full statistical model was published previously.

Brieﬂy, the I

statistic was calculated to conﬁrm the heterogeneity of the 2 RCTs. The

mortality hazard rate was used to evaluate all-cause mortality in the

pooled data set. Stata/IC version 15.1 (StatCorp LLC) was used to

perform a 2-stage meta-analysis of the patient-level data.

Continuous variables were assessed by the t test. Categorical vari-

ables were assessed by Fisher exact test and are presented as mean 

standard deviation or median (IQR range). Kaplan-Meier (KM) meth-

odology was used to estimate the hazard rate of all-cause mortality, and

the log-rank test was used to compare outcomes. Cox proportional

hazards modeling was utilized to identify predictors of mortality from 25

candidate variables. A univariable Cox model was developed for each

candidate variable. A P value of <.25 was required for entry into the

multivariable model, which was performed to adjust for confounding

variables. Variables were eliminated stepwise until the P value for each

was <.05. Two additional multivariable models were developed with

paclitaxel forced into the model, either as dose or exposure. Hazard

ratios (HRs) and 95% CIs were calculated. A P value of <.05 was

considered statistically signiﬁcant. SAS version 9.4 (SAS Institute) was

used for all statistical analyses except data mapping and heterogeneity

assessments.

Results

Demographic and baseline characteristics

After pooling from the ILLUMENATE Pivotal and EU RCTs, the

analysis population consisted of 589 patients (419 in the Stellarex arm

and 170 in the PTA arm). The demographic and baseline characteristics

have been published previously and are shown in Supplemental

Tables S1 and S2.

Although characteristics were generally similar be-

tween treatment arms, patients treated with the Stellarex DCB were

more often smokers (P ¼ .05) and were younger (P ¼ .02) but were less

often treated for recurrent lesions (P ¼ .04). The median follow-up was

4.9 years (IQR, 4.8-5.1 years).

Combining data sets

An I

statistic was calculated to assess the heterogeneity of the

ILLUMENATE Pivotal and EU RCTs. The studies were shown to be

congruent and were combined (I

¼ 0; P ¼ .893).

2 S.P. Lyden et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100634

All-cause mortality

The vital status compliance was 93.8% across the ILLUMENATE RCTs.

Follow-up was balanced between patients treated with the DCB (93.3%

averaging 1660 days) and those treated with PTA (94.6% averaging 1663

days). Table 1 shows the KM point estimates each year. At 1 year, the KM

estimate of freedom from all-cause death was 97.8%  0.72% (95% CI,

96.4%-99.2%) in the DCB arm compared with 98.8%  0.84% (95% CI,

97.1%-99.9%) in the PTA arm. At 2 years, the respectiverates were 93.0%

 1.3% (95% CI, 90.5%-95.5%) versus 95.2%  1.7% (95% CI, 91.9%-

98.4%). At 3 years, 90.3%  1.5% (95% CI, 87.4%-93.2%) versus 90.3% 

2.3% (95% CI, 85.8%-94.8%). At 4 years, 85.6%  1.7% (95% CI, 82.2%-

89.0%) versus 86.0%  2.7% (95% CI, 80.7%-91.3%). At 5 years, the KM

estimates of freedom from all-cause death were 80.4%  2.0% (95% CI,

76.7%-84.3%) in the Stellarex DCB arm compared with 80.4%  3.1%

(95% CI, 74.3%-86.5%) in the PTA arm. There were no differences in all-

cause mortality between the 2 arms throughout the full 5-year window

(log-rank, P ¼ .7754) (Central Illustration).

Paclitaxel dose and all-cause mortality

KM estimates of all-cause mortality were assessed for association

with nominal paclitaxel dose terciles. The mean nominal dosages were

classiﬁed as no paclitaxel (PTA; 0 mg) and low (0.1-3.2 mg), medium

(3.3-5.2 mg), and high (5.3 mg) paclitaxel doses. The respective KM

estimates of freedom from all-cause death were 80.4%  3.1%, 84.4%

 2.8%, 78.5%  3.8%, and 77.0%  3.8%. There were no statistically

signiﬁcant differences in KM estimates of freedom from all-cause death

assessed as a function of paclitaxel dose (log-rank, P ¼.5769) (Figure 1).

CEC-adjudicated causes of all-cause mortality

All causes of death were CEC-adjudicated (Table 2). At 5 years,

there were 80/419 (19.1%) deaths in the DCB arm and 32/170 (18.8%)

deaths in the PTA arm. Of the 80 deaths in the DCB arm, 16/80 (20.0%)

deaths were attributed to cardiovascular causes and 64/80 (80.0%) to

noncardiovascular causes. Of the 32 deaths in the PTA arm, 6/32

(18.8%) deaths were attributed to cardiovascular causes and 26/32

(81.3%) to noncardiovascular causes. There were no signiﬁcant differ-

ences in any Medical Dictionary for Regulatory Activities System of

Organ Class cause-speciﬁc deaths between patients treated with DCB

compared with PTA. No device- or procedure-related deaths were re-

ported in either arm.

Predictors of all-cause mortality in the DCB arm

The univariable analysis to assess predictors of death included 25

candidate baseline variables. Age, congestive heart failure, lesion

length, previous intervention, renal insufﬁciency, reference vessel

diameter, and smoking (protective) were found to be signiﬁcant pre-

dictors of mortality in the univariable model (Table 3). A multivariable

model was performed to adjust for confounding variables. Variables

were eliminated stepwise until the

P value

was <.05. In the ﬁnal

multivariable model (Table 4), predictors of mortality included renal

insufﬁciency (HR, 2.363; 95% CI, 1.530-3.650), larger reference vessel

diameter (HR, 1.244; 95% CI, 1.019-1.518), older age (HR, 1.052; 95%

CI, 1.031-1.074), and longer lesion length (HR, 1.005; 95% CI, 1.001-

1.009). When forced into the model, neither paclitaxel exposure (HR,

1.149; 95% CI, 0.761-1.734) nor dose (HR, 1.027; 95% CI, 0.959-1.100)

were found to be signiﬁcant predictors of mortality.

Discussion

This independent meta-analysis of 2 congruent RCTs from the

ILLUMENATE clinical program demonstrates that there was no statisti-

cal difference in all-cause mortality between patients treated with the

Stellarex DCB relative to PTA at any time point through 5 years. Vital

status was obtained for 93.8% of the patients for this analysis. Impor-

tantly, this patient-level analysis utilized rigorous methodology in the

largest, homogenous prospective RCT cohort of a single DCB.

Stellarex was approved by the FDA in 2017 for treating symptomatic

PAD. The coating consists of a polyethylene glycol excipient and a

hybrid formulation of paclitaxel. Paclitaxel is a cytostatic drug that in-

hibits smooth muscle cell proliferation and therefore prevents neo-

intimal hyperplasia.

11,12

At much higher concentrations than used to

coat DCBs and drug-eluting stents, paclitaxel is considered safe for

systemic cancer treatment, even in pregnant women.

Paclitaxel was

also considered safe to treat coronary disease

and was later expanded

to treat lesions in the periphery.

The late mortality signal that was ﬂagged by Katsanos et al

relation to paclitaxel exposure was a summary-level study of 28 RCTs

that assessed multiple devices with different concentrations and for-

mulations of paclitaxel as well as different excipients. Furthermore, data

from the ILLUMENATE RCTs were not included in the 5-year analysis

performed by Katsanos et al in 2018. Although a dose-dependent

mortality signal was suggested, the authors did not provide a plau-

sible mechanism to explain the causality, which was further hindered by

a paucityof data available at 2 and 5 years.Although acknowledging that

neither study was sufﬁciently powered to avoid type I error, it is important

to note that this current meta-analysis assessed mortality in patients

treated with a single device and included a similar number of patients in

magnitude (N ¼ 589) as the original 5-year mortality analysis performed

by Katsanos et al

(863 enrolled with follow-up in 679 patients).

This ﬁnal report of all-cause mortality from the pooled ILLUMENATE

RCTs builds on the previously established safety of the Stellarex DCB.

The primary safety and efﬁcacy end points of both the ILLUMENATE

Pivotal and EU were met and published previously.

6,7

In a meta-analysis

of the ILLUMENATE clinical program at 3 years

and the recent 4-year

data,

there was no difference in KM estimates of all-cause mortality

in patients treated with the Stellarex DCB relative to PTA. Furthermore,

the 5-year mortality analysis of the Stellarex DCB reported herein is

consistent with other long-term analyses of paclitaxel-coated bal-

loons

15,16

and several large observational studies of paclitaxel-coated

balloons in real-world patients.

17–25

In the present study, neither paclitaxel dose nor exposure was a

predictor of all-cause mortality at 5 years. The analysis identiﬁed age,

renal insufﬁciency, lesion length, and reference vessel diameter as

signiﬁcant predictors of death. However, because baseline character-

istics were collected preprocedurally for each treatment arm, it is un-

likely that the association of mortality with lesion length and/or

reference vessel diameter was related to paclitaxel exposure or dose.

This has been validated as there was no difference in KM estimates of

all-cause mortality in patients treated with PTA with low (0.1-3.2 mg),

medium (3.3-5.2 mg), or high (5.3 mg) doses of paclitaxel. Prior ana-

lyses from both the IN.PACT and Lutonix clinical programs

16,26

also did

not ﬁnd an association between all-cause mortality and increasing

paclitaxel dose in patients treated with the DCB. In general, the

Table 1. Kaplan-Meier point estimates of all-cause mortality.

DCB (n ¼ 419) PTA (n ¼ 170)

Year 1 (365 d) 97.8% (96.4, 99.2) 98.8% (97.1, 99.9)

Year 2 (730 d) 93.0% (90.5, 95.5) 95.2% (91.9, 98.4)

Year 3 (1095 d) 90.3% (87.4, 93.2) 90.3% (85.8, 94.8)

Year 4 (1460 d) 85.6% (82.2, 89.0) 86.0% (80.7, 91.3)

Year 5 (1825 d) 80.4% (76.7, 84.3) 80.4% (74.3, 86.5)

DCB, drug-coated balloon; PTA, percutaneous transluminal angioplasty.

S.P. Lyden et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100634 3

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predictors of mortality identiﬁed in this analysis are consistent with the

common risk factors that are persistent in this patient population.

In a recent study employing a similar methodology as Katsanos et

al,

Dinh et al

reported no difference in rates of all-cause mortality in

patients treated with paclitaxel versus uncoated devices at 1 year (34

studies, 7654 patients; relative risk ratio [RR], 0.99; 95% CI, 0.81-1.22; P

¼ .94), 2 years (20 studies, 3799 patients; RR, 1.16; 95% CI, 0.87-1.55; P

¼ .31), and 5 years (9 studies, 2288 patients; RR, 1.19; 95% CI,

0.98-1.45; P ¼ .08).

Based on the additional data that was available,

the authors concluded that there is no justiﬁcation to limit the use of

paclitaxel-coated devices for the treatment of femoropopliteal PAD.

A cross-industry supported patient-level meta-analysis by the VIVA

Physicians group corroborated the ﬁndings by Katsanos et al

in an

analysis of 8 RCTs with a median follow-up duration of 4 years. How-

ever, similar to Dinh et al

study, the HR diminished from 1.38 to 1.27

when the number of patients lost to follow-up was reduced from

19.6% to 9.5%, respectively.

A recent study of the Vascular Quality

Initiative showed that patients who received peripheral vascular in-

terventions and were lost to follow-up had an increased risk of mor-

tality (HR, 6.56; 95% CI, 6.16-6.99) at 1 year compared with patients

who completed their 1-year follow-up.

This suggests that although

patients may be randomized in clinical studies, those that miss

follow-up may show important differences in demographic charac-

teristics. As such, these ﬁndings highlight the importance of ascer-

taining complete vital status data for any paclitaxel DCB mortality

analysis.

Central Illustration.

Survival in the Pooled RCTs. The pooled RCTs show no signiﬁcant differences in Kaplan-Meier survival estimates between Stellarex DCB and PTA through 5 years (log-rank, P ¼ .7754).

DCB, drug-coated balloon; PTA, percutaneous transluminal angioplasty; RCTs, randomized controlled trials.

Figure 1.

Survival in the Pooled Randomized Controlled Trials by Paclitaxel Dose Terciles. There were no differences in Kaplan-Meier estimates of all-cause mortality between paclitaxel dose

terciles or compared with PTA (log-rank, P ¼ .5769). PTA, percutaneous transluminal angioplasty.

4 S.P. Lyden et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100634

A subgroup analysis of the VOYAGER PAD

trial and an interim

analysis of the SWEDEPAD

trial, which had 99.6% and 100% vital

status ascertainment, respectively, each found no signiﬁcant difference

in all-cause mortality in patients treated with paclitaxel-coated devices

relative to controls. The ﬁnal results from the SAFE-PAD study, which

was designed with input from the FDA, will further evaluate the

long-term risk of all-cause mortality in Medicare beneﬁciaries with a

median follow-up duration exceeding 5 years.

Finally, it is important to consider the clinical beneﬁt offered by

paclitaxel-coated devices in the PAD population. In randomized trials,

paclitaxel-coated balloons have consistently demonstrated superiority

over PTA in terms of improved vessel patency and reduced rates of

clinically driven-target lesion revascularization.

5–7

In conjunction with

several patient-level analyses and real-world studies demonstrating that

an increased risk of mortality is not associated with using

paclitaxel-coated balloons, the established efﬁcacy of DCBs must be

considered when making clinical decisions about their continued use

for the treatment of PAD.

Limitations

This study was limited by randomization ratios leading to fewer

patients in the PTA arm of the analysis. Moreover, because of the study

design of each ILLUMENATE RCT, sp eciﬁc data on revascularization

was not always provided, and therefore it is likely that some patients in

the PTA arm were not necessarily paclitaxel naïve. Thus, the per-

centage of those patients that crossed over is possibly inaccurate, and

the true mortality of those with paclitaxel exposure is unknown.

However, in a previous crude analysis of crossover patients reclassiﬁed

accordingly to the paclitaxel treatment arm within the 2 ILLUMENATE

RCTs through 3 years, there was no mortality difference between co-

horts. Furthermore, the surface area of the balloon and the number of

devices used during the procedure were used to calculate the

maximum potential of paclitaxel exposure, but this may not represent

the true amount of paclitaxel actually delivered to the vessel wall.

Drug transfer to the vessel wall depends on many factors, including

lesion characteristics, blood ﬂow, and more. An additional limitation of

this analysis is that only all-cause mortality was assessed, and the study

did not examine additional safety outcomes such as nonfatal severe

adverse events or others. Furthermore, neither RCT was prospectively

powered to assess mortality. Finally, the results presented in this

manuscript cannot be generalized to other paclitaxel-coated balloons

because of the differences in design (eg, composition of paclitaxel,

excipients).

Conclusion

The primary safety and efﬁcacy end points of the ILLUMENATE

Pivotal and EU RCTs were previously met and published, and there were

no device- or procedure-related deaths attributed to treatment with

Table 2. Clinical events committee-adjudicated causes of mortality for

patients treated with Stellarex drug-coated balloon compared with

percutaneous transluminal therapy within 5 years (1825 days).

Cause of mortality DCB PTA Total P value

Cardiovascular 16/80 (20.0) 6/32 (18.8) 22/112 (19.6) >.9999

Non-

cardiovascular

64/80 (80.0) 26/32 (81.2) 90/112 (80.4) >.9999

Gastrointestinal

disorders

2/80 (2.5) 2/32 (6.3) 4/112 (3.6) .3220

General

disorders

0/80 (0.0) 0/32 (0.0) 0/112 (0.0) >.9999

Hepatobiliary

disorders

0/80 (0.0) 1/32 (3.1) 1/112 (0.9) .2857

Infections and

infestations

4/80 (5.0) 1/32 (3.1) 5/112 (4.5) >.9999

Injury/

poisoning/

procedural

1/80 (1.3) 0/32 (0.0) 1/112 (0.9) >.9999

Metabolism and

nutritional

2/80 (2.5) 2/32 (6.3) 4/112 (3.6) .3220

Neoplasms

benign,

malignant

21/80 (26.3) 5/32 (15.6) 26/112 (23.2) .3227

Nervous system

disorders

2/80 (2.5) 1/32 (3.1) 3/112 (2.7) >.9999

Renal and

urinary disorders

2/80 (2.5) 1/32 (3.1) 3/112 (2.7) >.9999

Respiratory/

thoracic/

mediastinal

5/80 (6.3) 1/32 (3.1) 6/112 (5.4) .6721

Vascular

disorders

4/80 (5.0) 0/32 (0.0) 4/112 (3.6) .5767

Undetermined 21/80 (26.3) 12/32 (37.5) 33/112 (29.5) .2579

Total deaths 80/419 (19.1) 32/170 (18.8) 112/589 (19.0) >.9999

Values are n/N (%).

DCB, drug-coated balloon; PTA, percutaneous transluminal angioplasty.

Table 3. Univariable predictors of mortality.

Covariate Hazard ratio (95%

conﬁdence interval)

P value

Age (per y) 1.06 (1.04-1.08) <.0001

Renal insufﬁciency

2.77 (1.81-4.23) <.0001

Smoking (current) 0.44 (0.27-0.71) .0009

Lesion length (per mm) 1.01 (1.00-1.01) .0060

Previous intervention 1.63 (1.12-2.38) .0112

Smoking (previous) 0.55 (0.35-0.89) .0137

Reference vessel diameter (per mm) 1.26 (1.03-1.55) .0241

Congestive heart failure 1.82 (1.05-3.13) .0316

Diabetes mellitus type 2 1.34 (0.92-1.95) .1292

Myocardial infarction 1.40 (0.89-2.21) .1425

Chronic obstructive pulmonary disease 1.39 (0.88-2.21) .1560

Diabetes mellitus 1.29 (0.89-1.88) .1787

Peripheral vascular disease 1.57 (0.79-3.11) .1940

Lesion type (de novo) 0.72 (0.41-1.25) .2420

ABI/TBI (increments of 1) 0.64 (0.29-1.44) .2796

Angina 1.32 (0.78-2.24) .3077

Paclitaxel dose (per mg) 1.04 (0.97-1.11) .3091

Calcium (none vs present) 1.22 (0.83-1.78) .3171

Hyperlipidemia 0.84 (0.55-1.28) .4097

Sex (male) 0.86 (0.59-1.27) .4522

Diabetes mellitus type 1 0.68 (0.16-2.77) .5863

Rutherford category 4 1.33 (0.46-3.81) .5956

Paclitaxel exposure 0.92 (0.61-1.37) .6719

Rutherford category 3 1.09 (0.70-1.69) .7127

Hypertension 1.07 (0.61-1.88) .8102

Renal insufﬁciency was deﬁned as dialysis dependency or serum creatinine

>2.5 mg/dL within 30 days of the index procedure.

ABI, ankle brachial index; TBI, tibial brachial index.

Table 4. Multivariable predictors of mortality.

Parameter Hazard ratio (95% conﬁdence

interval)

P value

Age (per y) 1.052 (1.031-1.074) <.0001

Renal insufﬁciency

2.363 (1.530-3.650) .0001

Lesion length (per mm) 1.005 (1.001-1.009) .0083

Reference vessel diameter (per mm) 1.244 (1.019-1.518) .0320

Multivariate predictors were chosen with a stepwise procedure using an entry

criterion of 0.25 and a stay criterion of 0.05.

Renal insufﬁciency was deﬁned as dialysis dependency or serum creatinine

>2.5 mg/dL within 30 days of the index procedure.

S.P. Lyden et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100634 5

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Stellarex DCB.

6,7

In the independent, pooled, patient-level meta--

analysis of the ILLUMENATE US Pivotal and EU RCTs reported herein,

there was no difference in all-cause mortality in patients treated with the

Stellarex DCB relative to PTA through the full 5-year follow-up. These

5-year data build on the previously reported safety of the Stellarex DCB

for treating symptomatic PAD.

Acknowledgments

The authors would like to acknowledge Chao Cheng, MS (Syntactx

LLC, New York, NY), who provided biostatistical support.

Declaration of competing interest

Sean Lyden is a consultant for Endologix, PQ Bypass, Boston Sci-

entiﬁc, Medtronic, BD, and Penumbra, a board member for VIVA Phy-

sicians, participates in research studies with Endologix, Gore, BD,

Bolton, Abbott, Penumbra, Boston Scientiﬁc, Merit, Contego Medical,

and holds stock options in Centerline Biomedical. Marianne Brodmann

is a consultant for Philips, Cagent, Biotronik, Boston Scientiﬁc, Med-

tronic, BD, Shockwave, Reﬂow Medical, Bolt Medical, and Cook Med-

ical and participates in research studies with Philips, Cagent, Biotronik,

Boston Scientiﬁc, Medtronic, BD, Shockwave, Reﬂow Medical, Bolt

Medical, and Cook Medical. Andrew Holden is a medical advisory

board member for Philips, Medtronic, Boston Scientiﬁc, and Gore and

participates in clinical research for Philips, Medtronic, Boston Scientiﬁc,

Gore, Cook, BD-Bard, Shockwave, Abbott, Intact, Reﬂow, Merit, and

Surmodics. Kenneth Ouriel is the chief medical ofﬁcer for NAMSA.

NAMSA is a Medical Research Organization that receives funds from

Philips for clinical research services. Trisha Tarra is an employee of

Philips. William Gray is a consultant for Philips. Henrik Schroeder re-

ported no ﬁnancial interests.

Funding sources

This work was supported by Philips North America.

Ethics statement and patient consent

This study protocol was approved by either an independent review

board or ethics committee at each site, and the study was conducted in

accordance with the Declaration of Helsinki. All patients provided

written consent.

Supplementary material

To access the supplementary material accompanying this article,

visit the online version of the Journal of the Society for Cardiovascular

Angiography & Interventions at 10.1016/j.jscai.2023.100634.

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Original Research

Hospital-Level Variability in Use of Intracoronary Imaging for Percutaneous

Coronary Intervention in the United States

Ali O. Malik, MD, MSc

, John T. Saxon, MD

, John A. Spertus, MD, MPH

Adam Salisbury, MD, MSc

, James A. Grantham, MD

, Kevin Kennedy, MS

Chetan P. Huded, MD, MSc

Saint Luke’s Mid America Heart Institute, Kansas City, Missouri;

University of Missouri Kansas City, Kansas City, Missouri

ABSTRACT

Background: Intracoronary (IC) imaging for percutaneous coronary intervention (PCI) is associated with better patient outcomes and carries a class IIA

guideline recommendation, but it remains rarely used. We sought to characterize hospital-level variability in IC imaging for PCI in the United States and to

identify factors that may explain this variability.

Methods: Patients who underwent PCI, with or without IC imaging, in the Nationwide Readmissions Database (2016-2020) were included. A regression

model with a random effect for site was used to generate the median odds ratio (MOR) of IC imaging use for a patient at one site vs another, sequentially

adjusting for procedural, patient, and hospital factors to examine the extent to which different factors account for this variability.

Results: The analytic cohort included 1,328,517 PCI procedures (patient mean age 65.8 years, 32.4% female, IC imaging used in 9.2%) at 1068 hospitals. The

median hospital use of IC imaging increased from 2.7% (IQR, 0.6-7.7) in 2016 to 6.3% (IQR, 1.7-17.8) in 2020. In 2020, the MOR for IC imaging during PCI

was 4.6 (IQR, 4.3-5.0), indicating a >4-fold difference in the odds of a patient undergoing IC imaging with PCI at one random hospital vs another. Adjusting

for procedure, patient, and hospital factors did not meaningfully alter the MOR.

Conclusion: The average US hospital uses IC imaging for <1 in 15 PCI procedures, with marked variability across hospitals. Strategies to increase and

standardize the use of IC imaging are needed to improve the quality of PCI in the United States.

Introduction

Coronary angiography has important limitations in the evaluation of

coronary artery dimensions, plaque characteristics, and the result of cor-

onary stent implantation.

1,2

Intracoronary (IC) imaging, with either intra-

vascular ultrasound (IVUS) or optical coherence tomography (OCT), to

guide percutaneous coronary intervention (PCI) offers more accurate

measurement of vessel dimensions, lesion characterization to support

optimal vessel preparation, better stent sizing, and guidance of the

stenting strategy.

IC imaging also improves evaluation of the stent

expansion after implantation.

There is robust evidence from observa-

tional studies,

4,5

randomized controlled trials,

6–9

and meta-analyses

10,11

showingthat IC imagingimproves long-term clinical outcomes, including

cardiovascular death, myocardial infarction, target lesion revasculariza-

tion, and stent-thrombosis. Accordingly, IC imaging to optimize PCI was

assigned a class IIA guideline recommendation in the most recent

American College of Cardiology/American Heart Association coronary

revascularization guidelines.

Despite this, IC imaging to optimize PCI

was used in only 3% to 5% of PCI procedures in the United States in

2014-2015.

13,14

Although IC imaging rates have increased in recent

years,

hospital variability in the use of IC imaging for PCI and its asso-

ciation with procedural, patient, and hospital characteristics is not known.

Methods

Data source and study population

To obtain a national perspective of current PCI practice, we used

data from 2016 to 2020 from the Nationwide Readmissions Database

Abbreviations: CTO, chronic total occlusion; IC, intracoronary; ICD-10, International Classiﬁcation of Disease, Tenth Revision, Clinical Modiﬁcation/Procedure Coding System; IVUS,

intravascular ultrasound; MOR, median odds ratio; NRD, Nationwide Readmissions Database; OCT, optical coherence tomography; PCI, percutaneous coronary intervention.

Keywords: intracoronary imaging; percutaneous coronary intervention; quality improvement.

* Corresponding author: chuded@saint-lukes.org (C.P. Huded).

https://doi.org/10.1016/j.jscai.2023.100973

Received 16 March 2023; Received in revised form 27 March 2023; Accepted 28 March 2023

Available online 19 May 2023

the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100973

(NRD) of the Healthcare Cost and Utilization Project, adhering to

methodological standards set by the Healthcare Cost and Utilization

Project.

The NRD includes discharges for patients in a year and those

who have died in the hospital. The NRD includes data from 31 states for

the year 2020. These data account for 62.2% of the US resident pop-

ulation and 60.8% of all hospitalizations. However, the NRD does not

comprise a random sample of US hospitals, and the ﬁndings within this

cohort may not be fully representative of the entire US population. The

NRD includes all discharge records of patients treated in US community

hospitals, excluding rehabilitation and long-term acute care facilities.

All patients who underwent PCI were included in the analysis. Patients

from hospitals with a PCI volume <10 procedures/year were excluded.

Patients who had a PCI during the hospital stay were identiﬁed using

the International Classiﬁcation of Disease, Tenth Revision, Clinical

Modiﬁcation/Procedure Coding System (ICD-10).

Outcomes assessment

The primary outcome of interest was the use of IC imaging for PCI.

This was identiﬁed using ICD-10 codes for IVUS and OCT, respectively.

Supplementary Table 1 details all the ICD-10 codes used for data

abstraction.

Covariates

Patient demographic characteristics, socioeconomic status, comor-

bidities, and hospital characteristics are provided by the NRD. Hospital

bed size was categorized as small, medium, and large, depending on

number of beds, teaching status, and location as speciﬁed by the NRD

criteria

(Supplementary Table 2). Procedural characteristics (PCI for

myocardial infarction, ST-segment elevation myocardial infarction, and

non–ST-segment elevation myocardial infarction), presence of a chronic

total occlusion, and use of atherectomy were abstracted using ICD-10

codes. Most of the covariates, as well as our study outcome (IVUS or

OCT use), have multiple ICD-10 codes. We determined the covariate or

our study outcome to be present for a PCI procedure if any of these

codes (for a particular covariate or outcome) were listed.

Statistical analysis

Baseline patient and hospital characteristics in the analytical cohort

were described using mean and SD for continuous variables and fre-

quency (%) for categorical variables. Due to the large sample size (for

procedures), baseline characteristics were compared using standard-

ized mean difference. By convention, standardized mean differences of

greater than 10% are considered signiﬁcant.

For each hospital, we examined the proportion of PCI procedures

with use of IC imaging for each year of analysis. To explore trends in the

use of IC imaging for PCI, we plotted the use of any IC imaging (IVUS or

OCT), as well as the individual modalities of IVUS or OCT, over time

(2016-2020).

The NRD assigns a unique identiﬁer for each hospital each year, so it

is not possible to evaluate the performance of one hospital over

sequential years. Hence, hospital-level variability in the use of IC im-

aging was analyzed separately for each year. In this manuscript, we

present the analysis for the year 2020, with analyses for years 2016-2019

in the Supplementary Material. An unadjusted hierarchical logistic

regression model with random effects for hospitals was ﬁrst con-

structed, using the outcome of IC imaging during PCI as the dependent

variable. To describe variability in IC use across hospitals, we calculated

median odds ratio (MOR), which quantiﬁes the average difference in the

likelihood that 2 statistically identical patients would receive IC imaging

at one random hospital as compared with another. For example, a MOR

of 1.4 would mean that a similar patient would have a 40% higher odds

of having IC imaging when treated at one hospital vs another.

Moreover, to understand better how the addition of procedural, pa-

tient, and hospital factors affected the ability of the model to predict

outcome (use of IC imaging), we also calculated a c-statistic for each of

our models. The c-statistic is a unitless index that measures the good-

ness of ﬁt of a regression model, and values >0.7 indicate a good

model.

To identify how procedural, patient, and hospital characteristics

might inﬂuence the variability in the use of IC imaging, we sequentially

adjusted the logistic regression model for these factors and created

subsequent models after each level of adjustment. We obtained an

estimate of the variance explained by the addition of these factors using

the c-statistic. Model 1 was the unadjusted evaluation of variability in IC

imaging between hospitals without risk adjustment. Next, we incor-

porated procedural factors, which may be associated with higher

complexity and greater propensity to use IC imaging. Use of atherec-

tomy devices was selected as a readily identiﬁable procedural variable

and a reliable surrogate for heavy vessel calciﬁcation. Acute myocardial

infarction and presence of a chronic total occlusion were also selected

given the established beneﬁts of IC imaging in these populations.

5,20,21

To assess whether these procedural characteristics accounted for the

observed variability in IC imaging use, we added these procedural

factors to model 1 to create model 2 and obtained a new c-statistic. To

explore whether patient factors (demographic characteristics [age, sex],

socioeconomic status [mean household income, insurance status],

comorbidities [diabetes, hypertension, chronic kidney disease, previous

myocardial infarction, PCI, or coronary artery bypass grafting])

accounted for some of the observed variability, we then added these

factors to model 2 to create model 3. Finally, we adjusted for hospital

factors (bed size, teaching status, academic vs private, rural vs urban

location, annual PCI volume) to create a fourth model and calculated

Table 1. Baseline characteristics for the analytical cohort (N ¼ 1,328,517

procedures) stratiﬁed by patients who received intracoronary imaging versus

those who did not.

IC imaging

used

n ¼ 122,081

IC imaging

not used

n ¼ 1,206,436

Standardized

difference (%)

Demographic characteristics

Age, y 65.712.4 65.812.3 0.7%

Female sex 31.4% 32.5% 2.4%

Comorbidities

Diabetes 39.9% 40.8% 1.7%

Obesity 21.1% 21.1% 0.1%

Hypertension 54.9% 58.6% 7.5%

Systolic heart failure 22.1% 18.7% 8.4%

Smoking 49.0% 49.9% 1.8%

Prior MI 19.9% 17.8% 5.4%

Chronic kidney disease 22.4% 21.0% 3.4%

Prior PCI 21.4% 20.5% 2.2%

Prior CABG 8.0% 10.1% 7.1%

Pulmonary disease 19.1% 19.2% 0.4%

Socioeconomic status

Median household income (based on zip code)

1st quartile 23.8% 28.5% 17.3%

4th quartile 25.1% 19.0% –

No medical insurance 3.7% 4.0% 4.6%

Procedural characteristics

CTO 7.7% 6.8% 3.3%

MI (STEMI) 2.6% 3.2% 3.6%

MI (NSTEMI) 39.5% 40.8% 2.6%

Atherectomy used 15.1% 8.7% 19.8%

Values are mean  SD or %.

CABG, coronary artery bypass graft surgery; CTO, chronic total occlusion; IC,

intracoronary; MI, myocardial infarction; NSTEMI, non–ST-elevation myocardial

infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation

myocardial infarction.

2 A.O. Malik et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100973

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10.10.20268 Мб0Книга_3922_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20268 Мб0Книга_3924_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20268 Мб0Книга_3925_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20268 Мб0Книга_3926_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20268 Мб0Книга_3927_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20268 Мб0Книга_3928_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20267 Мб0Книга_3929_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20267 Мб0Книга_3931_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20267 Мб0Книга_3932_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20267 Мб0Книга_3934_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20267 Мб0Книга_3936_Библиотеки_им_академика_М_И_Перельмана.pdf