Keywords chronic limb-threatening ischemia - peripheral arterial disease - endovascular
Introduction
Lower limb peripheral arterial disease (PAD) is a leading cause of cardiovascular
morbidity.[1 ] Chronic limb-threatening ischemia (CLTI) occurs in the context of PAD, where the
blood supply to the extremity is unable to match the tissue resting metabolic needs
resulting in the more severe presentation with patients suffering from ischemic rest
pain and/or tissue loss for a period greater than 2 weeks.[2 ] Clinically this grade of disease is staged as Rutherford categories 4 to 6.[3 ] Endovascular treatment is well-established in the management of CLTI[4 ]
[5 ]
[6 ] with endovascular-first approaches featuring positively in the BASIL-2 trial and
presenting as lower risk alternatives to bypass surgery-first approaches, particularly
in comorbid patients.[5 ]
[7 ]
Restenosis is a frequent concern with any revascularization procedure.[8 ] For example, neointimal hyperplasia can result in restenosis following plain balloon
angioplasty.[9 ] The adjunctive use of drug-coated balloons (DCBs)—devices coated with antiproliferative
agents which reduce neointimal hyperplasia and subsequent vessel restenosis[10 ]
[11 ]—is increasing as part of revascularization strategies to avoid this barotrauma-related
phenomenon and decrease the associated late lumen loss.[12 ]
[13 ] Until recently, all commercially available DCBs for the treatment of PAD used the
cytotoxic drug paclitaxel as the antiproliferative agent.[14 ] However, in 2020, the 6 month primary end-point results were published from the
first-in-human clinical trial of a new DCB, called the SELUTION SLR (M.A. MedAlliance
SA, Nyon, Switzerland), used to treat femoropopliteal lesions in PAD patients.[15 ] The antiproliferative coating for the SELUTION SLR is the cytostatic drug sirolimus
(rapamycin), which had not previously been used on balloons for the treatment of peripheral
vasculature lesions.[14 ] The 6 months results were promising, and the SELUTION SLR has since become commercially
available for endovascular treatment of PAD.
Occlusive lesions are more difficult to treat, and are less likely to remain patent,
than stenotic lesions.[8 ] The length of the lesion also has a bearing on patency postintervention. A study
found that patients with a chronic total occlusion longer than 10 cm had a lower primary
patency rate.[16 ] Calcification also poses an independent issue with regard to restenosis[17 ]; it limits the delivery and absorption of the antiproliferative agent in DCB angioplasty.[18 ]
[19 ] Directional atherectomy has been shown to be a useful vessel preparation technique
while also reducing the risk of dissection and bailout stenting associated with angioplasty
of particularly heavily calcified vessels.[20 ]
[21 ] In addition, performing atherectomy prior to the use of a DCB has been shown to
improve patency.[16 ]
[22 ]
[23 ] The use of the rotational atherectomy devices Jetstream (Boston Scientific, Marlborough,
Massachusetts, United States) and Phoenix (Philips Healthcare, Cambridge, Massachusetts,
United States) rather than directional atherectomy is also reported to result in low
rates of distal embolization.[24 ]
[25 ]
This single-center retrospective study reports the results on the safety and efficacy
of a sirolimus drug-coated balloon (SELUTION SLR) for endovascular treatment, following
rotational atherectomy, in native occluded femoropopliteal lesions in patients with
CLTI.
Materials and Methods
Study Population and Design
This is a single-center, retrospective pilot study analyzing a cohort of CLTI patients
with femoropopliteal artery occlusions who were treated with atherectomy and postatherectomy
angioplasty using the SELUTION SLR device. As this was a retrospective analysis, ethical
approval was not required, but as per standard of care, all patients included in the
study gave their written informed consent for both the procedure and for use of their
patient data (including any imaging) for research purposes. The study was fully compliant
with the ethical principles outlined in the Declaration of Helsinki.
All patients who had undergone endovascular treatment of the native, occluded femoropopliteal
region for CLTI (Rutherford categories 4-6) with rotational atherectomy followed by
SELUTION SLR between April 1, 2021 and January 31, 2022 were identified from the radiology
information system. Inclusion criteria were as follows: documented CLTI in the electronic
patient record prior to procedure; target lesion in the femoropopliteal region; target
lesion treated with atherectomy followed by at least one SELUTION SLR balloon (as
documented in procedural notes); and target lesion must have been fully occluded pre-procedure
(as documented by preprocedural ultrasound angiology investigations or initial procedural
angiogram). Exclusion criteria included patients treated for an in-stent restenosis/occlusion;
hypercoagulation disorders; and cases where administration of anticoagulant or antiplatelet
medications is contraindicated.
Data Collection
The hospital Electronic Patient Records, e-Noting, and Picture Archiving and Communication
System (PACS) programs were reviewed to obtain baseline clinical information and procedural
details for all patients that met the inclusion criteria. The same electronic platforms
were then used to search the postprocedure period for each patient to record outcome
events. Follow-up imaging performed in external hospitals was requested and imported
to the local PACS.
Outcome Measures
Where appropriate, primary and secondary outcome measures were recorded at 6 and 12
months. The primary outcome measure was amputation-free survival (AFS) with amputation
defined as major (above the ankle) amputation of the index limb or death from any
cause. Secondary outcome measures were as follows: technical success defined as flow
restoration of the target lesion with residual stenosis less than 30%; 30-day mortality;
overall survival; 30-day morbidity (including access site complications, target vessel
reocclusion, major adverse cardiovascular event, any amputation of index limb); minor
amputation (below the ankle) of the index limb; major amputation (above the ankle)
of the index limb; major adverse limb event defined as major amputation of the index
limb or any further major reintervention of the treated segment (new bypass graft,
jump/interposition graft revision, or thrombectomy/thrombolysis); major adverse cardiovascular
event defined as myocardial infarction, transient ischemic attack, stroke or death
from any cause; limb salvage defined as the preservation of the index limb with no
major amputation; primary patency defined as uninterrupted vessel patency on imaging
with no re-intervention; primary-assisted patency defined as patency from the time
of reintervention due to restenosis (without reocclusion) of the target lesion; secondary
patency defined as patency from the time of reintervention due to reocclusion of the
target lesion; and binary vessel restenosis defined as reduction in at least 50% of
the vessel diameter.
Interventional Procedure
All procedures were performed in either an angiography laboratory or a hybrid operating
theatre.
The SELUTION SLR DCB is an over-the-wire 0.018-inch guidewire percutaneous angioplasty
balloon catheter with a coating of sirolimus at a dose density of 1µg/mm.[2 ]
[14 ]
[26 ] The sirolimus is mixed with a biodegradable polymer and a phospholipid blend to
form the coating that aims to achieve a sustained release of sirolimus as well as
optimize drug transfer to the vessel wall.[14 ]
[26 ] In this study, SELUTION SLR DCBs of 3 to 6 mm diameter were used.
Two atherectomy devices were available to the operators, Jetstream (Boston Scientific,
Marlborough, Massachusetts, United States) and Phoenix (Philips Healthcare, Cambridge,
Massachusetts, United States). Both devices feature a rotational atherectomy system
with an aspiration mechanism to remove any debris created. The Jetstream atherectomy
system is a rotational device that actively aspirates debris to avoid distal embolization;
it also gives the operator control as to when the blades are engaged to allow for
atraumatic manipulation within the vessel.[27 ] The Phoenix atherectomy system is also a rotational advice and employs the principle
of the Archimedes screw to prevent distal embolization of debris.[28 ] Both devices are used over a wire.
Statistical Analysis
Continuous variables are summarized as mean ± standard deviation, with categorical
variables summarized using frequency counts and percentages. Kaplan-Meier (K-M) analyses
were used to estimate outcome measures at 6 and 12 months, and expressed as % ± Standard
error of the mean. All statistical analysis was performed using GraphPad Prism (version
9.4.0 for Windows, GraphPad Software, San Diego, California, United States).
Results
Nine of the CLTI patients (see [Fig. 1 ]) treated in the department between April 1, 2021 and January 31, 2022 were found
to meet the inclusion criteria (mean age: 64.0 ± 8.4 years, 66.7% male). As shown
in [Table 1 ], a number of comorbidities were present in the cohort including diabetes mellitus,
hypertension, chronic heart failure, previous myocardial infarction, and previous
stroke. A third of the patients were Rutherford category 4 at baseline and the remaining
were Rutherford category 5 or 6. As per the inclusion criteria, all nine patients
were treated for a native occluded vessel in the femoropopliteal region using SELUTION
SLR balloons postatherectomy.
Table 1
Patient demographics and baseline clinical data
Variable
Number of patients
9
Age (mean ± SD)
64.0 ± 8.4
Male gender
6/9 (66.7%)
Diabetes mellitus
7/9 (77.8%)
Hypertension
6/9 (66.7%)
Chronic heart failure
2/9 (22.2%)
Previous MI
1/9 (11.1%)
Previous stroke
1/9 (11.1%)
CKD > Stage 3
0/9 (0.0%)
COPD
1/9 (11.1%)
Current malignancy
1/9 (11.1%)
Peptic ulcer
0/9 (0.0%)
Dementia
0/9 (0.0%)
Hemiplegia
0/9 (0.0%)
Baseline CRP (mean ± SD)
50.7 ± 41.9
Baseline systolic BP (mean ± SD)
135.7 ± 21.4
Baseline eGFR (mean ± SD)
72.0 ± 23.9
Baseline CLTI stage/category
- Ischemic rest pain (Rutherford 4)
3/9 (33.3%)
- Tissue loss (Rutherford 5/6)
6/9 (66.7%)
Abbreviations: BP, blood pressure; CKD, chronic kidney disease; CLTI, chronic limb-threatening
ischemia; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; eGFR,
estimated glomerular filtration rate; SD, standard deviation.
Fig. 1 Flowchart of cohort selection. CLTI, chronic limb-threatening ischemia; DCB, drug-coated
balloon.
Baseline lesion characteristics and a comparison of baseline versus postprocedural
infrapopliteal runoff are shown in [Table 2 ].
Table 2
Baseline lesion characteristics and arterial runoff
Leg treated
- Left
5/9 (55.6%)
- Right
4/9 (44.4%)
Lesion length (mm) (mean ± SD)
141.1 ± 145.6
Site of lesion
- SFA
5/9 (55.6%)
- Popliteal
3/9 (33.3%)
- Both
1/9 (11.1%)
Baseline runoff
Postprocedural runoff
No arteries
4/9 (44.4%)
No arteries
0/9 (0.0%)
One-vessel runoff
3/9 (33.3%)
One-vessel runoff
5/9 (55.6%)
Two-vessel runoff
1/9 (11.1%)
Two-vessel runoff
2/9 (22.2%)
Three-vessel runoff
1/9 (11.1%)
Three-vessel runoff
2/9 (22.2%)
Abbreviations: SD, standard deviation; SFA, superficial femoral artery.
One death occurred during the postprocedure period on day 178; however, no patients
underwent a major index limb amputation. Our primary outcome measure, AFS, has a K-M
estimate of 88.9 ± 10.5% at both 6 and 12 months. Technical success rate was 100%
and there were no intraprocedural complications. Thirty-day mortality was 0%. K-M
estimates for overall survival at 6 and 12 months were both 88.9 ± 10.5%. Two patients
(22.2%) underwent minor amputations on day 6 and 11 postprocedure, respectively. No
other adverse clinical events occurred in any patients during the first 30-day postprocedure;
therefore, 30-day morbidity was 22.2%. No further minor amputations occurred during
the study period. Major AFS was 100% at 12 months. Two patients (22.2%) underwent
further major revascularization interventions of the treated segments (on day 163
and 365 postprocedure, respectively). The only cardiovascular event was the one death
within the cohort. As no patients underwent a major index limb amputation, limb salvage
was 100%. K-M estimates for all outcome measures are shown in [Table 3 ], with survival curves for selected outcome measures shown in [Fig. 2 ].
Fig. 2 Kaplan-Meier curves for (A ) amputation-free survival (AFS; %), (B ) major adverse limb event (MALE)-free survival (%), (C ) minor AFS (%), (D ) primary patency, (E ) secondary patency (%), and (F ) freedom from binary restenosis.
Table 3
Kaplan-Meier estimates for outcome measures
6 months (% ± SEM)
12 months (% ± SEM)
AFS
88.9 ± 10.5
88.9 ± 10.5
Overall survival
88.9 ± 10.5
88.9 ± 10.5
Major AFS
100.0
100.0
Minor AFS
77.8 ± 13.9
77.8 ± 13.9
MALE free survival
88.9 ± 10.5
74.1 ± 16.1
MACE free survival
88.9 ± 10.5
88.9 ± 10.5
Primary patency
87.5 ± 11.7
75.0 ± 15.3
Secondary patency
100.0
100.0
Freedom from binary restenosis
76.2 ± 14.8
50.8 ± 17.7
Abbreviations: AFS, amputation-free survival; MACE, major adverse cardiovascular event;
MALE, major adverse limb event; SEM, standard error of the mean.
Two patients (22.2%) were found to have reocclusions of the treated vessel during
the postprocedure period on day 155 and 246, respectively. As described above, both
patients underwent revascularization procedures after the reocclusions were identified;
both vessels were patent at latest follow-up (day 356 and 50 post redo angioplasty,
respectively) giving secondary patency rates of 100% at 6 and 12 months. No cases
qualified for primary-assisted patency. Six target vessels (66.7%) were found to have
restenosed during the postprocedure period.
Discussion
The data from this retrospective observational study show no periprocedural and early
period safety concerns relating to the combination use of rotational atherectomy and
postatherectomy sirolimus-DCB angioplasty; there were no immediate procedural complications
and no major adverse clinical events attributable to the therapy within 30 days of
procedure. In addition, the 6 and 12 months clinical outcome and efficacy results
are promising and within acceptable rates.
More specifically, in 2009, the SVS-CLI Working Group published a set of “objective
performance goals” (OPGs) that were benchmark values for various clinical end-points
against which novel endovascular therapies could be measured.[29 ] These OPG values for 1-year postprocedure were AFS 71%; survival 80%; and limb salvage
84%. When compared with these values, the K-M estimates from our cohort (at 1-year:
AFS 88.9%; overall survival 88.9%; limb salvage 100%) present favorably.
The cause of death for the single diseased patient was sepsis secondary to infected
leg ulcers caused by peripheral vascular disease. The patient had, with capacity,
declined an above-knee amputation for the infection and had been referred to palliative
care. The patient was a 76-year-old comorbid female and was the oldest in the cohort.
She presented at baseline with tissue loss of the index limb, had the highest baseline
C-reactive protein (103), the lowest baseline estimated glomerular filtration rate
(37), and demonstrated no arterial runoff at baseline. She went on to have first,
second, and third toe amputation of the index limb on day 6 postprocedure. However,
on latest imaging (day 31 postprocedure), the target vessel was still patent with
no binary restenosis, and so, our conclusion is that this death was very unlikely
to have been attributable to our index therapy.
With regard to the other minor amputation, this patient was a 54-year-old diabetic
male who had also presented with tissue loss of the index limb. He had a very long
lesion (380mm) extending from the mid-superficial femoral artery into the popliteal
artery with no arterial runoff at baseline. He underwent a transmetatarsal amputation
of the index limb on day 11 postprocedure; however, on the latest follow-up imaging
(day 508 postprocedure), the target vessel still showed primary patency (albeit showing
binary restenosis at this time). Both minor amputations occurred shortly after the
index procedures, and it is deemed that these were likely inevitable despite the endovascular
interventions.
In terms of patency data, Zeller et al[15 ] in their first-in-human trial of the SELUTION SLR for the treatment of femoropopliteal
lesions presented a primary patency rate of 88.4% at 6 months that compares well with
our 6-month K-M estimate of 87.5 ± 11.7%. Zeller et al[15 ] also presented a 6-month freedom from binary restenosis rate of 91.2% for which
our K-M estimate (76.2 ± 14.8%) compares less favorably. However, the cohort in the
study by Zeller et al were Rutherford categories 2 to 4, with lower comorbidity rates
than our cohort, only 30% had total occlusions, lesion lengths were all less than
or equal to 150mm, and all patients had to have at least one patent infrapopliteal
artery at baseline. In addition, they were not investigating the combination therapy
of atherectomy and postatherectomy angioplasty; theirs was an investigation solely
of SELUTION SLR angioplasty.
In their 2021 PRESTIGE study, Tang et al[26 ] published 6-month outcomes from their investigation of using the SELUTION SLR balloon
for the treatment of tibial occlusive lesions in patients with CLTI. Despite this
study differing from ours in terms of the vessels of interest and the treatment protocol
(the use of sirolimus balloon angioplasty without atherectomy), the cohort characteristics
were very similar, and so it is interesting to compare their data with this study.
At 6 months, primary tibial patency was 81.5% and AFS was 84.0%, which again compares
well with the K-M estimates we present above, 87.5 and 88.9%, respectively. In their
report of the 12-month outcomes of the PRESTIGE study,[30 ] both primary tibial patency and AFS rates had held at 81.5 and 84.0%, respectively.
Our K-M estimates at 12 months of 75% primary patency and 88.9% AFS are again interesting
to compare.
Also in 2021, Feng et al[16 ] published their 6- and 12-month primary patency data from an investigation of directional
atherectomy combined with paclitaxel-coated balloon angioplasty of femoropopliteal
artery lesions in patients with PAD (Rutherford categories 2-6). Although their cohort's
comorbidities were similar to ours, 28% of patients only had stenoses and the average
length of the lesion was much shorter, at an average of 83 mm compared with 141 mm
in this study. In addition, this was not an investigation of just CLTI patients; indeed
34.2% of patients did not have CLTI; therefore, comparing results with our own is
not a comparison of two identical cohorts. Nevertheless, the work by Feng et al[16 ] does present the most similar treatment technique to our own. At 6 and 12 months,
K-M estimates for primary patency were 93.3% (95% confidence interval [CI]: 82.7–97.2%)
and 80.8% (95% CI: 67.3–79.7%), respectively. Again, this is interesting to compare
with our own results at 6 and 12 months of 87.5 ± 11.7% and 75.0 ± 15.3%, respectively.
While less favorable, it is important to note that the lesions treated were considerably
more severe, therefore, our results remain encouraging. A comparison of all values
presented in this section is provided in [Table 4 ].
Table 4
Comparison of outcome measures
Primary patency (% ± SEM)
Freedom from binary restenosis (% ± SEM)
AFS (% ± SEM)
Vascular territory
CLTI patients only?
Total occlusions only?
Treatment
6 months
12 months
6 months
12 months
6 months
12 months
Sumner et al
87.5 ± 11.7
75.0 ± 15.3
76.2 ± 14.8
50.8 ± 17.7
88.9 ± 10.5
88.9 ± 10.5
Fem-Pop
Yes
Yes
Atherectomy + sirolimus DCB (SELUTION SLR)
Zeller et al15
88.4
–
91.2
–
–
–
Fem-Pop
No
No
Sirolimus DCB (SELUTION SLR)
Tang et al30
81.5
81.5
–
–
84.0
84.0
Tibial
Yes
Yes
Sirolimus DCB (SELUTION SLR)
Feng et al16
93.3 (95% CI 82.7–97.2)
80.8 (95% CI 67.3–79.7
–
–
–
–
Fem-Pop
No
No
Atherectomy + paclitaxel DCB
Abbreviations: AFS, amputation-free survival; CI, confidence interval; CLTI, chronic
limb-threatening ischemia; DCB, drug-coated balloon; SEM, standard error of the mean.
Until the end of 2019, all commercially available DCBs for the treatment of PAD used
the cytotoxic drug paclitaxel as their anti-re-stenotic agent.[14 ] An antimicrotubular, cytotoxic agent, paclitaxel was originally approved as an antineoplastic
treatment for carcinomas in the 1960s.[31 ] It is thought that the antiproliferative effects of paclitaxel are a result of the
drug's cytotoxic effects in the smooth muscle cells.[31 ] However, in 2018 a meta-analysis suggested that PAD patients treated with paclitaxel-coated
devices (either stents or balloons) had higher all-cause mortality than patients treated
with bare (noncoated) devices, at both 2 and 5 years.[32 ] It has been suggested that this possible increased risk of late mortality may be
due to long-term, low-level exposure to the cytotoxic paclitaxel.[14 ]
[32 ] Although the conclusions of the meta-analysis were very controversial, with multiple
more recent studies finding no increased mortality associated with paclitaxel-coated
device use,[33 ]
[34 ]
[35 ] this has led to an inevitable loss of confidence in paclitaxel-devices among vascular
physicians.[14 ]
Sirolimus, in contrast to paclitaxel, is a cytostatic agent and was first approved
by the U.S. Food and Drug Administration in 1999 as Rapamune, used for the purpose
of preventing organ transplant rejection.[14 ] It was later incorporated into drug-eluting stent (DES) technology due to its antiproliferative
vascular effects for use in the coronary vasculature[36 ] and later in the peripheral vasculature for treatment of PAD.[15 ] Thus, while a relatively new player in the setting of DCBs in peripheral vasculature,
many DES studies have demonstrated its safety and efficacy and have now become a well-established
antiproliferative drug-coating used for endovascular procedures in both the coronary
and peripheral vessels.[14 ] While the efficacy of sirolimus over paclitaxel is still subject to investigation,
with only limited pilot studies published on DCBs in the peripheral vasculature,[31 ] it has been suggested that it has a preferential therapeutic safety margin compared
to paclitaxel and it has become the preferred drug coating for devices used in coronary
artery intervention.[31 ]
[37 ] This could be setting a precedent for what is to occur in the peripheral vascular
field. If sirolimus is to become the preferred drug-coating for DCBs used in peripheral
vascular disease, investigation into its combined use with other techniques and devices
is just as critical.
The combination of DCB and atherectomy especially in heavily calcified lesions is
beneficial for several reasons. As discussed previously, the technical success rate
of endovascular treatment of stenoses is greater than occlusions.[38 ] By “downgrading” the lesion from an occlusion to a stenosis by debulking the lesion
with atherectomy, long-term patency rates may be increased. The use of a DCB following
atherectomy also has the potential to reduce neointimal hyperplasia as a result of
the traumatic effects of atherectomy on the intima and therefore reduce restenosis
rates.[22 ] Lastly, by debulking the calcific portion of the plaque with atherectomy drug transfer
from the DCB to the vessel wall is improved.[19 ]
Limitations
The small cohort size is an important limitation and extrapolation should be exercised
with caution. Procedural protocol also varied between operators and the use of two
different atherectomy devices, while similar, may further affect the outcomes.
Conclusion
This single-center retrospective pilot study has analyzed the outcomes of a cohort
of CLTI patients with native femoropopliteal artery occlusions treated with rotational
atherectomy and postatherectomy angioplasty using the SELUTION device. This study
was designed as a pilot investigation to gain an initial insight into the safety and
efficacy of the combination therapy in a particular disease setting. The combined
use of sirolimus DCBs and atherectomy for the treatment of femoropopliteal occlusions
is a safe and effective technique yielding satisfactory patency and adverse event
rates. Overall, this calls for larger scale studies to compare the efficacy of this
management algorithm against other treatment protocols.
