Intravascular Lithotripsy and Drug-Coated Balloon Angioplasty for Severely Calcified Common Femoral Artery Atherosclerotic Disease

Abstract

Objectives:

Intravascular lithotripsy (IVL) followed by drug-coated balloon (DCB) angioplasty might be a valuable alternative to surgery for calcified common femoral artery (CFA) atherosclerotic disease. Nonetheless, the 12 months performance of this treatment strategy remains unknown. This study reports on the 12 months outcomes of IVL with adjunctive DCB angioplasty for calcified CFA lesions.

Methods:

This is a retrospective single-center, single-arm study. Consecutive patients treated by IVL and DCB for calcified CFA disease between February 2017 and September 2020 were evaluated. The primary measure outcome of this analysis was primary patency. Procedural technical success (<30% stenosis), freedom from target lesion revascularization (TLR), secondary patency, and overall mortality were additionally analyzed.

Results:

Thirty-three (n=33) patients were included in this study. The majority presented with lifestyle limiting claudication (n=20, 61%), 52% (n=17) of the patients had chronic kidney disease (CKD) and 33% (n=11) had diabetes. The procedural technical success was 97% (n=32). A flow-limiting dissection post IVL was observed in 2 patients (6%) and a peripheral embolization in a single patient (3%), while the bail-out stenting rate amounted to 12% (n=4). No perforation was observed. The median length of hospital stay was 2 days (interquartile range 2–3). At 12 months, the primary patency was 72%. The freedom from TLR and the secondary patency rates were 94% and 88%, respectively. The 12-month survival amounted to 100% and 75% (n=25) of the patients were asymptomatic or presented with mild claudication. The presence of chronic limb-threatening ischemia (CLTI) (hazard ratio [HR], 0.92; confidence interval (CI); 0.18–4.8, p=0.7) or CKD (HR, 1.30; 95% CI, 0.29–5.8; p=0.72), as well as the use of a 7 mm IVL catheter (HR, 0.59; 95% CI, 0.13–2.63; p=0.49) or of high-dose DCB (HR, 0.68; 95% CI, 0.13–3.53; p=0.65) did not influence the primary patency.

Conclusions:

In this study, the combination of IVL and DCB angioplasty for calcified CFA disease was associated with low risk for periprocedural complications, acceptable 12 months clinical outcomes, and low rates of reinterventions.

Clinical Impact

Intravascular lithotripsy in combination with DCB angioplasty can be an alternative to surgery in highly selected patients with CFA atherosclerotic disease. In this Cohort the combination therapy lead to acceptable clinical results and low reintervention rates at 12 months.

Introduction

Endovascular treatment has evolved rapidly over the last decades and is currently considered the firstline treatment option for most atherosclerotic lesions of the peripheral vasculature. ¹ However, primary open repair remains the standard of care for common femoral artery (CFA) atherosclerosis. Main reasons are the high technical success and the durability of CFA endarterectomy in the long run.^2–4 Nevertheless, surgical revascularization of the groin vessels is not as benign as previously believed, given the increased risk for periprocedural morbidity and mortality.^5,6 A retrospective analysis of 1843 patients who underwent surgical revascularization of the groin observed a 3.4% postoperative mortality, 8% wound-related complications, and a 15% risk of combined mortality/morbidity while >60% of these events occurred after discharge. ⁶ Thus, there is a growing interest for the development and adaption of endovascular solutions for CFA disease. ²

The use of plain old balloon angioplasty (POBA), scaffolds, and drug-coated balloon (DCB) angioplasty with or without debulking has been previously described for CFA lesions.^7–11 Nonetheless, the risk for jailing the deep femoral artery or losing an access vessel, as well as the severe calcification, which is frequently observed in the groin, still challenge the performance of endovascular treatment. ¹² In addition, as current recommendations suggest against the use of scaffolds for CFA disease, a calcium dedicated “leave-nothing-behind” approach might be a valuable alternative to surgery. ¹³

Intravascular lithotripsy (IVL), which uses pulsatile sonic waves to fracture intimal and medial calcification, is associated with promising periprocedural outcomes and low rates of complications in patients with CFA disease.^14,15 Moreover, the combination of IVL and DCB seems to reduce the need for reinterventions for femoropopliteal lesions. ¹⁶ However, the midterm performance of IVL with adjunctive DCB for CFA disease remains unknown. This analysis reports on the 12 months outcomes of IVL with anti-restenotic therapy for calcified CFA lesions.

Materials and Methods

Study Design

This study is a single-center, retrospective analysis of prospectively collected data, performed in line with the requirements of the local ethics committee and adhering to the Declaration of Helsinki. All patients provided informed consent prior to the intervention.

Patients treated by IVL and DCB for calcified CFA lesions between February 2017 and September 2020 were included into this study. Patients with isolated aortic, iliac, Superficial femoral artery (SFA), or popliteal lesions were excluded from this analysis. Individuals treated with IVL as stand-alone therapy or IVL in combination with scaffolds were additionally excluded.

Patient baseline characteristics, imaging, and clinical data were prospectively collected and retrospectively analyzed. Follow-up visits were performed at 6 and 12 months after the index procedure and annually thereafter. Duplex ultrasound scanning was used to assess the patency of the treated vessels unless symptoms warranted angiography or non-invasive imaging.

Dual antiplatelet therapy with aspirin (100 mg/d) and clopidogrel (75 mg/d) was prescribed for 8 weeks, followed by aspirin or clopidogrel lifelong. Patients previously taking direct oral anticoagulants or warfarin were maintained on the anticoagulant with an additional antiplatelet therapy for 8 weeks after the procedure. A triple therapy with dual antiplatelet medication and oral anticoagulation was not recommended. A statin therapy lifelong was suggested.

Study Device and Procedural Protocol

The Shockwave Medical Peripheral IVL System (Shockwave Medical, Santa Clara, CA) has been described elsewhere. ¹⁵ Briefly, the IVL catheter produces a series of sonic pressure waves, which pass through a fluid-filled balloon and selectively disrupt the calcified plaque of the intima and media. Lithotripsy is administrated in 30 pulse cycles, and every IVL catheter can deliver up to 300 pulses. For femoropopliteal lesions, a slight oversizing of the IVL catheter is suggested (1.1:1 compared with nominal vessel diameter). The currently available M5 and the M5+ peripheral IVL catheters house 5 lithotripsy emitters and are 60 mm long. The devices are available in multiple diameter sizes ranging from 3.5 to 8.0 mm in 0.5 mm increments and are compatible with a standard 0.014 inch guidewire. During the study period, only the M5 catheter was available; thus, the 7 mm IVL device was the largest used. A predilation with an undersized POBA catheter can be performed in patients with chronic total occlusions (CTOs) or tight stenosis to enable the crossing of the device. Regarding lesions affecting the deep femoral or proximal SFA, sizing was based on the presence or absence of CFA disease. If the CFA is patent, then the selected IVL catheter should be slightly oversized compared with the nominal diameter of the profunda. If the plaque extends from the CFA to the deep femoral, we select the catheter based on the CFA nominal diameter. The IVL catheter is then activated at 2 atm instead of 4 atm when treating the affected branch. The same algorithm is followed in patients with plaques extending in the proximal SFA.

A paclitaxel-coated DCB was used following the vessel preparation with lithotripsy (Figure 1). The selection of the IVL and DCB catheters was left to the discretion of the treating physician. Flow-limiting dissections or residual stenosis >50% were treated by prolonged (>3 minutes) POBA. Provisional (bail out) stenting with interwoven stents was used to treat major flow-limiting dissections or significant recoils (>30% restenosis after DCB angioplasty). A distal protection device was not routinely used. In case of proximal SFA and deep femoral disease, no kissing IVL or DCB angioplasty was applied. In some procedures, a second 0.014 guidewire was used to secure the access to both vessels of the femoral bifurcation.

Figure 1.

IVL and DCB angioplasty for common femoral artery disease. IVL, intravascular lithotripsy; DCB, drug-coated balloon.

Endpoints and Definitions

The primary measure outcome of this study was primary patency, defined as freedom from significant restenosis or occlusion without any reintervention. Secondary outcomes were secondary patency rate, freedom from clinically-driven target lesion revascularization (TLR), procedural technical success, and overall survival.

Significant restenosis was indicated by a >2.0 peak systolic velocity ratio calculated as the peak systolic flow velocity in the lesion divided by the peak systolic velocity 1 cm proximal to the lesion. Secondary patency was defined as restored flow in the treated segment after occlusion or restenosis. A major amputation was defined as any above-ankle amputation. Procedural technical success was defined as residual stenosis <30% in the absence of arterial perforation and flow-limiting dissection of the treated segment, while technical success post IVL as a residual stenosis <50% without perforation. The severity of calcification burden was assessed based on the Peripheral Arterial Calcium Scoring Scale (PACSS). Grade 0 represents the lack of visible calcium at the target lesion, grade 1 refers to unilateral calcification shorter than 5 cm, grade 2 refers to unilateral wall calcification longer than 5 cm, grade 3 shows the presence of bilateral wall calcification shorter than 5 cm, and finally grade 4 is defined as bilateral wall calcification with calcium extension longer than 5 cm. ¹⁷ Six grades of dissection (A–F) were identified. Type A was defined as dissection with minor radiolucent areas, type B as linear dissection, type C as dissection with contrast agent outside the lumen, type D as spiral dissection, type E as persistent filling defects, and type F as vessel occlusion without distal antegrade flow. Severe vessel dissection patterns were defined as type C or higher. ¹⁸

Statistical Analysis

Summary descriptive statistics are presented as mean ± SD, or frequencies and %, as appropriate. Repeated-measures analysis of variance (ANOVA) was employed to assess ankle brachial index (ABI) course from baseline to discharge and follow-up. Paired-samples t test was used to assess changes of Rutherford score from baseline to follow-up. Kaplan-Meier product limit estimate time to (1) primary patency (PP), (2) TLR, and (3) secondary patency (SP) curves were constructed and compared across various subgroups with log-rank tests. The 95% confidence interval (CI) for 1 year patency free rates were also constructed. All statistical analyses were carried out at the 2-sided 5% level of significance, using IBM-SPSS 26.

Results

Baseline Characteristics

Thirty-three (n=33) patients were included in this study. The majority (n=20, 61%) presented with lifestyle limiting claudication (Rutherford 3), 52% (n=17) of the patients had chronic kidney disease (CKD), 33% (n=11) had diabetes, and 33% (n=11) had a previous intervention at the index limb. The mean ankle brachial index at baseline was 0.61 ± 0.37. A CTO was observed in 4 patients (12%), and the median lesion length was 56 mm (interquartile range [IQR]: 42–70). Regarding the severity of calcification, 2 lesions were classified as PACSS 1 (6%), 27% of the lesions were PACSS class 2 (n=9), 49% PACSS class 3 (n=16), and 18% PACSS 4 (n=6). A deep femoral artery involvement was observed in 6 patients (n=6, 18%), and a proximal SFA disease in 14 (n=14, 42%). A single vessel tibial run-off was observed in 9 patients (27%), a 2-vessel rung off in 17 patients (52%), while all 3 tibial vessels were patent in 7 patients (21%). Table 1 provides an overview of the baseline characteristics of the study population.

Table 1.

Patient’s Characteristics.

Characteristics	Results
Total number	33
Men Mean age (± SD), in years	17 (52%) 73 ± 10
Arterial hypertension	31 (94%)
Dyslipidemia	20 (61%)
Diabetes mellitus	11 (33%)
Congestive heart disease	16 (49%)
Chronic kidney disease	17 (52%)
End-stage renal disease	1 (3%)
Cerebrovascular disease	6 (18%)
Smoking (current)	2 (6%)
Smoking (past)	10 (30%)
Rutherford classes
Class 3	20 (61%)
Class 4	11 (33%)
Class 5	2 (6%)
Class 6	1 (3%)
Chronic limb-threatening ischemia	14 (42%)
Mean Ankle Brachial Index (ABI) (± SD)	0.67 ± 0.39
Previous intervention	11 (33%)

Early Outcomes

The post-IVL technical success rates amounted to 94% (n=31), while the procedural technical success was 97% (n=32). No target lesion perforation was observed. The rates of peripheral embolization and flow-limiting dissection were 3% (n=1) and 6% (n=2), respectively, whereas the final angiogram revealed a non-flow-limiting dissections in a single patient (3%). A bail-out interwoven stent (Supera, Abbott, Santa Clara, CA) was deployed in 4 lesions (12%) either due to a flow-limiting dissection or significant recoil. No relevant plaque swift was observed in lesions involving the femoral bifurcation. The median postoperative ABI at discharge was 0.9 (IQR, 0.6–1.00). A high-dose DCB (In.Pact Admiral, Medtronic, Dublin, Ireland) was used in 22 procedures (57%), while a low-dose DCB catheter (Stellarex, Phillips/Spectranetics Corp., Colorado Springs, CO, and Ranger, Boston Scientific, Marlborough, MA) was used in 11 patients (33%). A concomitant iliac intervention was performed in 9 patients (27%), while 7 (21%) patients underwent simultaneous femoropopliteal interventions beyond the target lesions and 3 a tibial revascularization (9%). Iliac disease was treated with primary stenting, while tibial vessels were treated with angioplasty ± bail-out drug eluting stent (DES) deployment. Regarding femoropopliteal disease, 5 patients underwent IVL and DCB angioplasty, a single patient was treated by DCB angioplasty for an in-stent-restenosis, while a covered stent was deployed in the SFA for a perforation following POBA. The median hospital stay (IQR) was 2 (2–3) days.

Outcomes in Follow-Up

The mean clinical follow-up time was 13.5 ± 8.6 months. The primary patency at 12 months amounted to 72% (95% CI, 49%–86%) (Figure 2). The freedom from TLR at 12 months was 94% (95% CI, 78%–98%) and the secondary patency rate 88% (95% CI, 66%–96%). The freedom from major amputation was 100%, and the overall survival rate amounted to 100% at 12 months. At follow-up, 2 patients were treated by endarterectomy of the CFA, while a third patient underwent a repeated IVL/DCB angioplasty procedure. Regarding the clinical status of the study cohort at the last follow-up (Figure 3), most patients (n=25, 75%) were either asymptomatic or complained about mild claudication (Rutherford class 1–2), 5 patients (16%) had severe claudication (Rutherford class 3), 1 (3%) ischemic rest pain (Rutherford class 4), and 2 patients (6%) had persistent tissue loss (Rutherford class 5–6). All patients presenting with chronic limb-threatening ischemia (CLTI) at follow-up had a critical limb ischemia at baseline. For the Cox-regression analysis, univariate analyses between patients with and without patency loss and with and without TLR was performed. The presence of CLTI, CKD, CTO, or PACSS 3/4 lesions did not increase the risk for patency loss or TLR, while neither the use of a 7 mm IVL catheter or high-dose DCB influence the outcomes of the patients (Table 2).

Figure 2.

Seventy-two percent primary patency of intravascular lithotripsy and drug-coated balloon angioplasty at 12 months.

Figure 3.

(a) Rutherford class distribution at baseline. (b) Rutherford class distribution at last FU. Significant shift (p>0.001) in Rutherford scale, decreased from an average of 3.5 to 1.8 during FU. All but 2 patients had lower Rutherford class during FU. FU, follow-up.

Table 2.

Univariate Hazard Ratios—Cox Regression Analysis.

Variable	Primary patency		TLR
	HR (95% CI)	p value	HR (95% CI)	p value
PACSS 3/4	0.69 (0.19–2.6)	0.59	1.8 (0.18–17.5)	0.60
CKD	1.8 (0.46–7.4)	0.39	0.96 (0.14–6.8)	0.96
CLTI	0.99 (0.24–4.0)	0.99	2.14 (0.3–15.3)	0.45
CTO	0.04 (0–129.1)	0.43	0.04 (0–7.035)	0.59
DCB high dose	0.92 (0.19–4.4)	0.91	0.83 (0.09–8.1)	0.88
7 mm IVL	1.58 (0.42–5.9)	0.49	3.75 (0.4–36.1)	0.22

Abbreviations: CI, confidence interval; CKD, chronic kidney disease; CLTI, chronic limb-threatening ischemia; CTO, chronic total occlusion; DCB, drug-coated balloon; HR, hazard ratio; IVL, intravascular lithotripsy; PACSS, Peripheral Arterial Calcium Scoring Scale; TLR, target lesion revascularization.

Discussion

Atherosclerotic lesions of the CFA and its branches is still considered a primary surgical domain, given the excellent results of CFA endarterectomy on the long run. ¹⁹ However, the presence of non-independent functional status, preoperative dialysis, sepsis, or dyspnea at rest increases the risk for perioperative mortality, while a higher perioperative morbidity is observed among older individuals and in patients with diabetes, obesity, and chronic steroid use.^5,6 Consequently, an endovascular approach might be offered in these high-risk subgroups. In this cohort, the use of IVL and DCB for calcified CFA lesions was associated with low rates of periprocedural complications and reinterventions and acceptable 12 months clinical outcomes.

The severe calcification, which is frequently observed in patients with de novo atherosclerotic lesions of the groin, challenges the outcomes of endovascular therapy. The IVL is a calcium dedicated modality, which has been used for the treatment of peripheral lesions both as stand-alone therapy and as vessel preparation tool. Two studies have already reported on the periprocedural outcomes of IVL for CFA disease. In the initial analysis of the Disrupt PAD III observational registry, 12.5% of the patients were treated for CFA lesions, and in 70.4% of these cases, an adjunctive DCB angioplasty was applied. The mean posttreatment residual stenosis was less than 30%, and no significant complications were reported. ¹⁴ In a CFA-specific cohort, Brodmann et al evaluated the performance of IVL in 21 patients treated in 3 centers. The posttreatment mean diameter stenosis was 21.3%, 5 non-flow-limiting dissections were observed, and none of the participants experienced a perforation, distal embolization, or thrombotic occlusion of the treated vessels. ²⁰ Furthermore, a case series of 54 lesions evaluated the risk for TLR following IVL with and without DCB angioplasty for CFA lesions. In this cohort, DCBs were not used in all cases, while additional atherectomy was performed in 39% of the lesions. Despite the inhomogeneity of this cohort, the authors reported a low periprocedural complication rate and a cumulative freedom from TLR of 80.6% at 18 months. Nonetheless, no information was provided regarding the patency of the treated vessels. ²¹ Similar to these reports, our analysis showed a high technical success and a low incidence of periprocedural complications.

Drug-coated balloon angioplasty has been used in this study as anti-proliferative therapy to reduce the risk for restenosis and repeated interventions. A single-center experience reporting on the performance of IVL and DCB for femoropopliteal disease showed an added benefit from the adjunctive use of paclitaxel-coated devices compared with previously published data for IVL as stand-alone therapy.^15,16 Although, a head-to-head comparison cannot be performed, Stavroulakis et al reported for the combination treatment a primary patency of 81%, whereas in the DISRUPT PAD II trial, the use of IVL as stand-alone therapy showed a patency of 54%. Nonetheless, in the current analysis, a relatively high rate of patency loss has been observed despite the use of the anti-proliferative agent. The analysis of the DISRUPT II trial showed that an under sizing of the IVL catheter is associated with an increased risk for restenosis. For patients treated by the optimal technique, the TLR rate was 8.6%, while the overall rate of TLR amounted to 20.7%. ¹⁵ During the study period, the largest IVL catheter available on the market was 7 mm. A significant mismatch between the selected devices and the diameter of the target lesion might explain the relatively high rate of primary patency loss. Of note, in a retrospective analysis of patients treated by atherectomy and DCB for CFA disease, the authors found a significant mismatch between the target lesion reference diameter and the DCB used in a considerable number of interventions. Böhme et al ²² reported that after angiographic assessment, the diameter of the CFA can be up to 10 mm. The M5+ catheter which is currently available in sizes up to 8 mm might improve the outcomes of IVL in this vascular bed, but it might be still significantly undersized. In addition, after changing the compliance of the vessel wall with the endovascular lithotripsy, the use of an oversized POBA catheter might be considered to improve the luminal gain. However, despite the loss of patency based on duplex criteria, some patients remained asymptomatic, thus the freedom from TLR was rather high.

The use of DCB angioplasty as stand-alone therapy or in combination with debulking, POBA, and stent treatment has been already described for CFA lesions. In a study comparing the performance of DCB with surgery, there was a trend to fewer complications in the endovascular group but significantly higher risk for patency loss at 12 and 24 months. ²³ Given the poor performance of paclitaxel-coated devices in calcified disease, a vessel preparation strategy might be used prior to DCB angioplasty to treat calcium and increase the drug uptake in the vessel wall. ²⁴ However, there is no solid evidence that debulking prior to DCB is associated with better outcomes than debulking in combination with POBA or DCB alone.^8,22 Moreover, it is still unclear whether paclitaxel-coated balloons should be the anti-restenotic treatment of choice in heavily calcified lesions. ²⁴

Regarding stent deployment, the TECCO trial showed a lower risk for perioperative morbidity and mortality for patients treated with scaffolds, whereas the clinical, morphological, and hemodynamic outcomes of surgical and endovascular treatment were comparable at midterm. ¹⁰ The small number of patients included, and the lack of long-term follow-up are important limitations of this trial, despite the randomized control study design. The ongoing SUPERSURG trial will compare the outcomes of the Supera interwoven stent (Abbott Medical, Illinois, USA) with surgery for CFA disease (NCT04349657). The exclusion, however, of patients with severe medical comorbidities, advanced disease (Rutherford class 5 and 6), or occlusive lesions might limit the clinical relevance of this study.

Overall, the current body of evidence suggests that endovascular treatment might offer a benefit over surgery in terms of reduced perioperative complications, but open repair is associated with superior outcomes in the long run.^2,19 Future trials regarding CFA disease should evaluate the performance of different endovascular modalities and compare them with surgical treatment in the framework of a “best-endovascular” versus “best-surgical” study design.

Limitations

Although this is the first analysis reporting on the outcomes of peripheral IVL with adjunctive DCB angioplasty for calcified CFA disease, this study carries the well-known limitations of registries. The retrospective study design, the low number of patients included, the lack of a control group, and the absence of core laboratory adjudication are further limitations of this study. Finally, during the study period, the 7 mm M5 catheter was the largest device available. Consequently, the introduction and use of the M5+ might further improve the outcomes of IVL for CFA disease. Furthermore, surgical endarterectomy remains the gold standard for de novo CFA disease in our institution. In this study, we evaluated highly selected patients, who were either at very high risk for surgery (for local or systematic complications) or refused an open repair. Other modalities, like atherectomy with anti-restenotic therapy, are very valuable tools for patients with restenotic or fibrocalcific disease of the groin vessels. However, we do not consider them as first option for heavily calcified disease. Accordingly, a comparison of IVL and DCB angioplasty with surgery or other modalities would not be meaningful. Finally, there is a significant methodological limitation regarding the use of the PACSS score, which is developed to describe the calcification burden of femoropopliteal disease. However, this classification system might fail to describe the severity of the disease of the CFA, as the groin vessels are significantly shorter than the SFA and the plaque is mostly on the posterior wall of the vessel. Nonetheless, there is no commonly acceptable definition for the calcification burden of the groin vessels.

Conclusions

In this analysis, the use of IVL in combination with DCB for severely calcified CFA disease showed an excellent safety profile, low rate of reinterventions, and acceptable 12 months clinical outcomes. The potential benefit from other adjunctive therapies to IVL should be evaluated in the framework of prospective trials. Although surgery remains the gold standard for CFA disease, IVL with DCB might be offered in highly selected patients as alternative to open repair.