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12 Drug-Coated Balloons inInfrainguinal Arteries
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direct in-line blood ow to the foot in patients with nonhealing wounds or gangrene
(Class I) is recommended. However, strong evidence for the use of DCB in belowthe- knee interventions is still lacking.
In a meta-analysis of 6769 patients treated with infrapopliteal disease, primary
patency at 1year was 63%, 15% underwent repeat revascularization, and about the
same also underwent amputation and died as a result of all-cause mortality [62].
Possible challenges with tibial artery interventions include extensive calcications;
long, diffusely disease segments; large number of CTOs; inability to estimate true
vessel size; and, therefore, appropriate balloon sizing and possible loss of drug from
the DCB due to longer delivery time.
Several studies have explored the safety and efcacy of DCBs in infrapopliteal
disease. Table12.3 summarizes the major RCTs that assessed the use of DCBs in
major RCTs. Most of these trials are limited by a small sample size. The Drug-
Eluting Balloon Evaluation for Lower Limb Multilevel Treatment (DEBELLUM)
trial [63] which included 50 patients had about 25% below-the-knee lesions. At 6and 12-month follow-up, the DCB arm had signicantly lower LLL (0.5mm vs
1.6mm), TLR (6.1% vs. 23.6%), and binary restenosis rates (9.1% vs. 28.9%) compared to PTA.In addition, there was a signicant improvement in Fontaine class in
the DCB group compared to PTA (80% vs. 56%). The Drug-Eluting Balloon in
Peripheral Intervention for Below-the-Knee Angioplasty Evaluation (DEBATEBTK) trial evaluated patients with long lesions below the knee, and a signicant
proportion of them had occlusions (77–82%). In spite of these high-risk lesions,
there was still a superiority benet with the use of DCBs with respect to TLR and
binary restenosis rates at 12months [64].
These smaller trials which were followed by data from a large, multicenter
randomized trial in below-the-knee critical limb ischemia [65] failed to show any
signicant benet with the use of DCBs over PTA in the tibial arteries. In the
Randomized IN.PACT Amphirion Drug-Coated Balloon vs. Standard Percutaneous
Transluminal Angioplasty for the Treatment of Below-the-Knee Critical Limb
Ischemia (IN.PACT DEEP) trial, 358 subjects were randomized 2:1 to DCB
angioplasty with the IN.PACT Amphirion balloon or uncoated balloon angioplasty. The study demonstrated no signicant benet of DCB angioplasty over
uncoated PTA at 5years with respect to restenosis and TLR rates. This study also
assessed a safety endpoint of all-cause death up to 5years. While there was no
difference in all-cause death, there was a nonsignicant but 2.4-fold increased
risk of major amputations compared to the DCB group at 12months and at 5years
of follow-up [65].
More recently, the IN.PACT BTK study (presented as an LBCT at TCT Connect
2020) evaluated the efcacy of the IN.PACT 0.014 DCB (3.5μg/mm2) compared to
uncovered balloon angioplasty as a control. The study included patients with critical
limb ischemia (CLI) and CTOs of the infrapopliteal arteries and lesions that were
severely calcied and long (average length 17.6cm). The results were promising, as
the DCB group was associated with a 53% lower LLL compared to the PTA control
group, both in the subsegmental (across the entirety of the lesion) and the classic
LLL (at the narrowest segment of the artery) groups. In addition, there was no
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Table 12.3 DCB RCTs in infrapopliteal PAD
Treatment
groups
DEBELLUM
2014 [63]
DEABTEBTK 2013
[64]
IN.PACT
DEEP 2014
[65]
IN.PACT BTK
2020 (results
to be
published)
RCT 1:1
N=50
patients,
N=122
lesions
RCT, single
center
N=132,
158 lesions
RCT 2:1
N=358
Prospective
multicenter
RCT 1:1
N=104
IN.PACT
Amphirion
(3.5μg/mm2)
DCB vs.
PTA
75% fem-pop
lesions, 25%
below-theknee disease
IN.PACT
Amphirion
(3.5μg/mm2)
DCB vs.
PTA
IN.PACT
Amphirion
(N=239)
(3.5μg/mm2)
DCB vs.
PTA
(N=119)
IN.PACT
0.014 DCB
(3.5μg/mm2)
vs. PTA
S. A. Avadhani et al.
Avg.
lesion
length Primary EP Outcome
7.5cm LLL, TLR, and
restenosis rates at
6 and 12months
13cm
77–82%
CTO
10–
13cm
17.6cm LLL (classic and
TLR at 12months Superiority of
Freedom from
TLR at 5years
Safety composite
major amputation
and all-cause
mortality
subsegmental),
TLR at 9months
Safety EP of
device-/procedurerelated mortality
and freedom from
CD-TLR and
amputation at
9months
LLL 0.66 DCB vs.
1.69 PTA (0.03) at
6months BTK
TLR 12% vs. 35%
Amputation rate
4% vs. 12%
(p=0.36)
DCB vs. PTA
DCB with TLR
(18% vs. 43%),
binary restenosis
rates (27% vs.
74%) and
amputation rate
(0% vs. 1.5%)
DCB vs. PTA
Freedom from
TLR 68.6% vs.
78.4% and from
CD-TLR 70.9%
vs. 76% DCB vs.
PTA
Major amputation
rate (15.4% DCB
vs. 10.6% PTA
p=0.11)
MAE at 5years
60.8% vs. 58.4%
p=0.2 DCB vs.
PTA
Subsegmental LLL
0.59mm vs.
1.26-mm DCB vs.
PTA
Classic LLL
0.89mm vs.
1.31-mm DCB vs.
PTA
No sig. difference
in safety EPs
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signicant difference in the safety endpoints which included device- and procedurerelated death, major amputations, and clinically driven TLR at 9months.
In a network meta-analysis by Katsanos etal., the secondary endpoint of TLR in
infrapopliteal arteries demonstrated a signicant 40% reduction associated with
DCB use. The crude risk of TLR was 11.8% in the DCB group versus 25.6% in the
uncoated balloon group. The calculated pooled risk ratio was 0.53 (95% CI
0.35–0.81; p=0.004), with a corresponding number needed to treat eight patients
(95% CI 4–25) [66].
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DCB Use inOther Lesion Subsets: In-Stent Restenosis, Long
Lesions, andCombination Therapy
In-Stent Restenosis (ISR)
Outcomes for the treatment of ISR depends on the type of lesion—focal lesions,
classied as <5cm; diffuse, generally >5cm; and total occlusions [67]. In-stent
lesions that are total occlusions are usually associated with high recurrent ISR than
focal lesions in spite of the use of adjunctive therapies such as atherectomy [68].
Early studies from a single-center, Italian registry of 38 patients suggested successful treatment of SFA ISR with PTA followed by DCB post-dilation. This study
showed a 2-year patency rate (dened as proximal velocity ratio of <2.4) of 70.3%
in those treated with DCB [69]. This was followed by the Femoropopliteal In-Stent
Restenosis Repair: Midterm Outcomes After Paclitaxel-Eluting Balloon Use
(PLAISIR) trial, a small sample size prospective cohort study involving 53 patients
with femoropopliteal ISR treated with IN.PACT Admiral DCB, which was found to
have a 1-year patency rate of 84% and freedom from TLR of 90.2% [70]. Subsequent
studies [71–74] demonstrated the efcacy of DCB in treating ISR lesions; however,
these were limited by single-center studies and small study populations. These ndings are reviewed in Table12.4.
A meta-analysis by Cassese et al. included four RCTs which evaluated DCB
angioplasty for femoropopliteal ISR [75]. A total of 367 patients were followed for
a period of 12months. The study showed that DCB angioplasty resulted in a lower
risk of TLR, recurrent ISR, and sustained improvement in Rutherford class compared to plain balloon angioplasty. The DCB group had a lower risk for TLR (odds
ratio 0.20, p=0.002) and recurrent ISR (OR 0.24, p=0.003) and a sustained RC
improvement (OR 2.57, p=0.002) compared to PTA [75].
This was also conrmed from a subsequent patient-level meta-analysis (2532
patients and 16 RCTs) which showed superiority of drug-coated therapies in ISR
lesions [76]. The analysis compared multiple therapies including bare nitinol stents,
covered stents, paclitaxel, or sirolimus stents and paclitaxel balloons with plain balloon angioplasty in femoropopliteal ISR.Restenosis and TLR were the lowest in
paclitaxel stents and balloons, respectively, supporting the use of drug-coated therapies in in-stent restenotic lesions [76].
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Table 12.4 DCB use in in-stent restenotic lesions
Treatment
DEBATEISR 2014
[71]
FAIR 2016
[72]
PACUBA
2016 [73]
Trial
RCT
N=44
Diabetics+fempop ISR
Prospective
single-center
RCT 1:1
N=119
SFA ISR
Prospective,
dual-center RCT
N=74
ISR of fem-pop
lesions
arms
IN.PACT
admiral
(N=44)
(3.5μg/mm2)
DCB vs. PTA
(N=42)
IN.PACT
admiral
(3.5μg/mm2)
DCB vs. PTA
(admiral
Xtreme)
Freeway
balloon with
shellac
(3.0μg/mm2)
DCB (N=35)
vs. PTA
(N=39)
S. A. Avadhani et al.
Avg.
length Endpoints Outcomes
137cm Recurrent ISR,
TLE rate, up to
3years
82.2mm
29%
CTO
173mm 1° patency at
Restenosis at
6months and
1year
Freedom from
CD-TLR
All-cause
mortality at
12months
Thrombosis at
12months
12months (<50%
stenosis by duplex
or CTA without
TLR)
Complication rate
at 1month
Clinical success
(change in
Rutherford/ABI,
CD-TLR) at
30days
Recurrent ISR
19.5% vs.
71.8% DCB vs.
POBA
TLR 13.6% vs.
31%
At 3years: TLR
40% vs. 43% in
DCB vs. PTA
Restenosis at
1year 29.5%
vs. 62.5% DCB
vs. POBA
(p=0.004)
Freedom from
CD-TLR 90.8%
vs. 52.6% DCB
vs. POBA at
1year
(p=0.0001)
All-cause
mortality 4.3%
vs. 6.8%
(p=0.59) at
12month
40.7% vs.
13.4% DCB vs.
PTA patency
rate at
12months
p=0.02
Freedom from
CD-TLR 49%
vs. 22% DCB
vs. PTA,
p=0.11
Change in
Rutherford 69%
vs. 54.5% DCB
vs. PTA
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Table 12.4 (continued)
ISARPEBIS
2017 [74]
Dual-center RCT
1:1
N=70
SFA ISR
IN.PACT
admiral
(3.5μg/mm2)
DCB N=36
vs. PTA
N=34
139mm
36%
CTO
% diameter
stenosis at
6–8months
Binary restenosis,
TLR, amputation/
bypass surgery,
and all-cause
mortality at
24months
% diameter
stenosis 44%
vs. 65% at
6–8months
Binary
restenosis 30%
versus 59%
p=0.03
TLE 19% vs.
50% p=0.007
at 24months
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Long Lesions
Long femoropopliteal lesions remain a challenge for endovascular intervention with
patency rates of 35–50% and often complicated by restenosis that is difcult to treat
[77]. The SFA-Long study specically addressed the role of DCB therapy in long
femoropopliteal lesions [78]. The prospective, multicenter, single-arm study
included 105 patients who had lesions greater than 15cm (average lesion length
251mm) and followed them for a period of 12months. At follow-up, the patency
rate, dened as freedom from combined endpoints of CD-TLR and by duplex ultrasound, was 83.2% [78]. In addition, at 12months, there was a signicant improvement in the quality of life (measured by walking impairment questionnaire) and in
the ankle-brachial indices [78]. There was a 7% risk of adverse events which
included death from any cause, thrombosis, or nontarget vessel revascularization [78].
In the single-arm sub-study of 131 patients from the IN.PACT Global study [79]
with long and complex native ISR lesions (N=149 lesions, 59% calcied and 34%
CTOs), there was an 88% primary patency rate at 12 months treated with
DCB.Preliminary data conrmed the safety and efcacy of using DCBs in long and
complex ISR lesions in the femoropopliteal arteries [79]. Clinically driven TLR rate
was 7.2%, and freedom from device-/procedure-related events was 92.7% at
1year [79].
Combination Therapies
The increasing prevalence in the use of DCBs was accompanied with the development of several other therapies to address restenosis and improve patency rates in
PAD.Most RCTs evaluating the use of DCBs in PAD excluded the use of other
adjunctive therapies such as atherectomy, laser atherectomy, scoring balloons, and
stents in their trial subjects. Data regarding the use of these adjunctive therapies
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with drug-coated balloons is limited. Calcium presents a barrier to paclitaxel absorption as shown by Fanelli etal. which showed signicantly lower patency rates in
calcied lesions treated with DCB [41]. In addition, elastic recoil, incomplete stent
expansion, and dissections might affect the patency rates of balloon angioplasty,
especially in long and calcied lesions. Atherectomy appears to reduce the risk of
dissections and bailout stenting and improve acute procedural results [80, 81].
The Directional Atherectomy (HawkOne, Silver Hawk, TurboHawk Medtronic)
Followed by a Paclitaxel-Coated Balloon to Inhibit Restenosis and Maintain Vessel
Patency (DEINITIVE-AR) study rst evaluated if vessel preparation with atherec-
tomy prior to drug delivery improved outcomes [82]. It was suggested that plaque
modication with directional atherectomy might enable a more homogenous drug
delivery and increased penetration into the vessel wall [83]. In this pilot, prospective, multicenter randomized study of 102 patients, subjects were randomized to
treatment with DAART (directional atherectomy with anti-restenotic therapy) plus
DCB vs. DCB alone (Cotavance paclitaxel balloon with Paccocath coating, 3μg/
mm2) alone [80]. The mean lesion length was 106mm, and about 28% of them were
occlusions [80]. One-year primary outcome of angiographic percent diameter stenosis was 33.6% in the atherectomy + DCB arm vs. 36.4% in the DCB arm
(p=0.48). Primary patency and rates of major adverse events were similar between
the two groups demonstrating that the use of directional atherectomy prior to DCB
therapy was safe and effective [80]. The rate of ow-limiting dissections was lower
in the atherectomy plus DCB arm (2% vs. 19.4%, p=0.01) [82]. In a single-center
study of 78 patients, there was a statistically signicant difference between primary
patencies at 1year associated with the use of DAART which was 82% compared to
65% with DCB alone [83].
In the recently presented data from the prospective Directional Atherectomy and
DCB to Treat Long Calcied Femoropopliteal Lesions (REALITY study presented
at Vascular InterVentional Advances (VIVA) 2020, November 6–7, 2020) study of
102 subjects evaluated the use of TurboHawk (Medtronic) atherectomy in conjunction with DCB.Preliminary data demonstrated a 12-month primary patency rate (by
duplex ultrasound) of 77% and freedom from CD-TLR of 93% with the use of
directional atherectomy prior to DCB (IN.PACT Admiral DCB) for long, calcied
femoropopliteal lesions. The average lesion length was 17.9cm, 39% were CTOs,
and 86% had moderate-severe calcication.
Other debulking techniques, especially in the setting of in-stent restenosis, have
also been gaining traction. The use of laser atherectomy (Philips) to debulk the ISR
lesion, prior to the application of DCB, might help reduce restenosis and improve
patency. While laser atherectomy has been shown to improve patency rates compared
to PTA alone in the treatment of ISR [84], few studies have investigated its application with DCB.A dual-center observational study of 112 patients with Tosaka II–III
lesions [67] underwent laser atherectomy plus DCB treatment and compared with
laser atherectomy and plain balloon angioplasty. The use of DCB was associated
with a signicantly higher freedom from reocclusion (86.7% vs. 57.1%) and TLR
(72.5% vs. 50.5%) at 1year [85]. Further data from the currently enrolling Photo-Pac
trial by Zeller etal. might add additional information regarding this therapy.
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The use of orbital atherectomy (OA, CSI) in exvivo peripheral arteries demonstrated a 50% increase in radiolabeled paclitaxel uptake and deeper penetration
compared to the untreated segment in calcied plaque [86]. OA use was associated
with thinner intima and less plaque calcication [86]. OA with the use of DCB was
also investigated in a small retrospective study of 113 patients by Kokkinidis etal.
[87]. In patients with heavily calcied femoropopliteal lesions, there were similar
outcomes at 2years with the use of OA in addition to DCB treatment compared to
DCB alone (p=NS). The 2-year freedom from TLR was 76.1% in the OA plus
DCB group vs. 55.5% in the DCB alone group [87]. There was a signicantly lower
rate of bailout stenting in the OA group; however, other procedural outcomes and
complications were similar between the two groups.
More recently, the use of Jetstream atherectomy (JA) device (Boston Scientic),
a rotational cutter with aspiration capacity approved for treatment of calcied femoropopliteal disease, was evaluated in adjunction to DCB in the single-center JETSCE comparative study of 75 patients [88]. At 16months, there was a signicantly
higher freedom from TLR associated with JA and DCB use compared with JA plus
PTA (94.4% vs. 54%) [88]. The currently enrolling JET-RANGER randomized
study will provide additional information.
The use of drug-eluting stents with DCB remains controversial. While the use of
two different antineoplastic agents (paclitaxel-based balloons with limus-based
stents) might offer a potential option in complex or recurrent ISR lesions, there
remains concern about drug toxicity in overlap areas, incomplete endothelialization
of stent struts, and the need for longer duration of dual antiplatelet agents [89].
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Future Innovations inDCB Technology
A newer-generation, paclitaxel-coated SurVeil® DCB (Surmodics Inc.) was studied
in PREVEIL, a prospective, US, multicenter, feasibility trial at three different clinical
sites for the treatment of native femoropopliteal arteries. The lower-dose paclitaxel
DCB (2mcg/mm2 loading dose) uses an excipient that improves efcacy and uniformity of paclitaxel drug transfer and minimizes systemic doses. In total, 13 patients
were included with an average lesion length of 56 mm (Vascular InterVentional
Advances (VIVA) 2018, Las Vegas, NV). Median paclitaxel plasma concentration
peaked immediately post-procedure (Cmax 1.07 ng/mL) and was undetectable at
30 days (Vascular InterVentional Advances (VIVA) 2018, Las Vegas, NV). The
plasma concentration achieved was much lower than the currently available DCBs,
and there were no adverse events related to the drug or device reported. In addition,
there was an improvement in ABI by 0.28, improvement in 6-min walk test by 90.4m,
and improvement in Rutherford class by 69%. Primary patency was achieved in all
patients, LLL was 0.27mm, and there were no reported TLR at 6months (Vascular
InterVentional Advances (VIVA) 2018, Las Vegas, NV). Although not available for
clinical use in the United States, further larger trials including TRANSCEND RCT
that compares the SurVeil DCB to IN.PACT DCB are still pending.
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While sirolimus- and everolimus-coated stents have demonstrated safety and
efcacy in the treatment of femoropopliteal disease [90, 91], limus-coated balloons
offer a new alternative therapy for de novo and restenotic lesions. Given that limusbased, coronary stents have been shown to have more antiproliferative effect than
paclitaxel-based stents [92] and are the cornerstone of interventional therapies for
coronary artery disease, limus-based DCBs might offer the same benet. Sirolimus
is a cytostatic molecule that binds to the FKBP-12 molecule blocking cell cycle
progression from G1/S phase [93]. However, given short tissue retention time and
slow absorption, delivery of sirolimus for several weeks might be necessary for
effective inhibition or neointimal proliferation [94]. The physical properties of the
drug have made it difcult to be applied in DCB technology. Three sirolimus-coated
balloons have been developed for intracoronary use—Magic Touch (Concept
Medical) with a phospholipid excipient and carrier, the Virtue balloon (Orchestra
BioMed), and SELUTION (MedAlliance). These balloons are also being applied in
the peripheral vasculature.
The pilot SELUTION trial was a prospective, multicenter, single-arm trial that
assessed 6-month safety and efcacy outcomes of the SELUTION SLR DCB in
femoropopliteal arteries [95]. In this study of 50 subjects, outcomes including angiographic late lumen loss (LLL), binary restenosis, improvement in Rutherford class,
ankle-brachial index, and patency by duplex ultrasound were all in favor of DCB
over plain balloon angioplasty. The patency rate, measured by duplex ultrasound,
was 88.4%, and freedom from binary restenosis was 91.2% at 6months with the use
of DCB [95]. Longer-term data pertaining to the use of this DCB remains to be seen.
The ongoing XTOSI study by Edward Choke aims to study the application of the
Magic Touch, a sirolimus-coated DCB in femoropopliteal arteries in critical limb
ischemia.
Paclitaxel scoring balloons also offer an exciting new frontier in the treatment of
PAD.With the ability for simultaneous plaque modication and drug delivery, these
devices might offer better patency and restenosis rates compared to standard therapy. The recently approved Chocolate Touch DCB balloon was evaluated in the
ENDURE trial which included 67 patients, majority with Rutherford class III.The
6-month patency rate was 90% by Duplex ultrasound and LLL of 0.16mm, which
was improved compared to the Lutonix and Stellarex DCBs [90]. Final results
remain to be seen.
S. A. Avadhani et al.
Mortality andPaclitaxel
In December 2018, a study-level meta-analysis by Katsanos et al. [96], which
pooled data from 28 RCTs and included 4432 patients, found an increase in mortality associated with DCB use. While there was no statistically signicant difference
in 1-year mortality in the 28 RCTs, an increase in 2-year all-cause mortality was
reported based on 12 RCTs which persisted at 5years in 3 studies.
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Of the three RCTs (THUNDER, ZILVER-PTX, and IN.PACT SFA) with 5-year
follow-up, there was a 14.7% risk of death in the paclitaxel-treated arm vs. 8.1% in
the non-paclitaxel arm (6.6% absolute risk) [96]. The authors reported a doserelated increase in mortality postulated to be due to downstream embolization and
toxicity. However, the analysis was limited by study-level pooled data and the
absence of patient-level data including individual cause of deaths to establish a
causal relationship. The study was also limited by several RCTs that were underpowered to detect a mortality difference between the two groups, missing data
beyond 2years, crossover of treatment, and patients lost to follow-up. This led to an
FDA guidance to healthcare professionals that cautioned against the use of drugcoated balloons due to an increase in long-term mortality [97].
Following this, a 3-year patient-level meta-analysis of the ILLUMENATE trials
[98] was performed and failed to show any association of the Stellarex DCB with
mortality for up to 3years. In the meta-analysis, patient-level data from all patients
treated with Stellarex DCB from six studies were included. Of the 1906 patients that
were included, all-cause mortality was similar among the groups treated with DCB
and PTA [98]. All-cause mortality was 2.1% at 1year and 7.0% at 3years of follow up. Also, an independent patient-level meta-analysis of 1980 patients with 5-year
follow-up data of the IN.PACT Admiral DCB showed no association of paclitaxel
dose exposure and mortality [99].
Subsequently, an independent FDA analysis included the four RCTs (Zilver
PTX, LEVANT 2, IN.PACT SFA I and II, and ILLUMENATE) with available
5-year follow-up data and incorporated trials that were not part of the Katsanos
meta- analysis. A patient-level analysis by the FDA also found an increase in mortality associated with paclitaxel use, especially between 2 and 5 years (13.7% vs.
18.3% with DCB); however, this was limited by missing data of 14–38% in some
trials [100]. At the same time, the Vascular InterVentional Advances (VIVA) physicians group meta-analysis was performed, which included 2185 subjects from 8
paclitaxel trials with 4-year follow-up of patient-level data and recovered missing
data that was not included in the original meta-analysis. This study demonstrated a
4.6% absolute increase in all-cause death in patients treated with paclitaxel devices,
which was lower than previously reported [101]. In addition, there was no evidence
of drug dose-related exposure and mortality risk over 5years [101]. However, since
freedom from TLR and clinical improvement were still maintained, a full discussion of risks and benets related to paclitaxel devices was recommended by the FDA.
Following this data, several large observational studies including Vascular
Quality Initiative (VQI), OPTUM, and SAFE-PAD attempted to elucidate this mortality signal better. In the propensity-matched, Vascular Surgery VQI analysis of
8376 patients undergoing endovascular treatment of femoropopliteal disease, there
was no difference in mortality at 1 year between paclitaxel and non-paclitaxel
groups (9.6% vs. 12.6%, respectively) [102]. Mortality was lower in the paclitaxel
subgroup of patients with intermittent claudication; however, this was not signicant in the CLTI group [102]. A multicenter cohort of 16,560 patients from the
Centers for Medicare and Medicaid Services, by contrary, found a lower cumulative
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incidence of all-cause mortality among those treated with paclitaxel therapies in
femoropopliteal arteries (32.5% vs. 34.3%, p=0.007). After multivariate adjustment, there was no difference in all-cause mortality between the two groups including patients with CLI and among those treated with DCB alone or DES with or
without DCB [103]. This was also maintained among patients treated with DES
compared to BMS in a Medicare cohort of 51,456 patients (51.7% DES vs. 50.1%
BMS at 4.1years, p=0.16) [104]. Further data is awaited in the larger yet SAFEPAD observational retrospective study by Secemsky et al., which includes all
Medicare beneciaries undergoing lower extremity revascularization.
Additional independent analyses that included large registry data in Germany
also failed to show any association of mortality related to paclitaxel devices. In a
large, propensity-matched cohort of 14,738 patients, there was no evidence of
increase in mortality associated with paclitaxel use [105]. In a propensity-matched
model, there was a lower all-cause mortality, amputation, and cardiovascular death
in the paclitaxel cohort [105]. Freisinger etal. included all patients with BARMER
health insurance who underwent any paclitaxel-based therapy for PAD (64,771
patients) [106]. The study also found no association of paclitaxel-coated devices
with mortality for up to 11years posttreatment [106]. Surprisingly, during the rst
year of follow-up, there was a decrease in mortality with paclitaxel devices compared to uncoated devices (HR 0.92, p<0.001) which disappeared subsequently
[106]. In a retrospective analysis of a similar cohort of 37,914 patients from the
BARMER insurance group, a propensity score-matched analysis found an improved
overall and amputation-free survival in the paclitaxel-treated CLTI and intermittent
claudication (IC) groups [107].
The more recently published results of the SWEDEPAD [108] RCT also support
these ndings. In this randomized study, 2289 patients were randomized to drugcoated devices vs. uncoated therapies (65% with CLTI) and followed for 2–4years.
The multicenter trial was powered to detect a difference in the primary endpoint of
mortality between the two groups. During the follow-up period, there was no difference in all-cause mortality between the two groups. The overall mortality in the
DCB group was 10.4%. vs. 9.8% in the uncoated device group [108] which was not
signicant. The wealth of data since the publication of the meta-analysis by Katsanos
etal. continue to support that paclitaxel-coated devices are not associated with an
increase in all-cause mortality compared to uncoated devices (Fig.12.1).
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