Impact of “black rock” on clinical outcomes after endovascular therapy for de novo calcified femoropopliteal lesions

The relationship between severity of calcification and clinical outcomes after endovascular therapy (EVT) for femoropopliteal lesions is well known. We often encounter dense calcifications in our daily practice, which are darker than normal calcifications on angiography. Accordingly, we named it “black rock” (BR), and investigated its impact on clinical outcomes after EVT. We retrospectively analyzed 677 lesions in 495 patients who underwent EVT for de novo calcified femoropopliteal lesions at our hospital between April 2007 and June 2020. BR is defined as a calcification which is 1 cm or more in length, occupies more than half of the vessel diameter, and appears darker than the body of the femur on angiography. Propensity score matching analysis was performed to compare clinical outcomes between lesions with BR [BR (+) group] and without BR [BR (−) group]. A total of 119 matched pairs of lesions were analyzed. Primary patency at 2 years was significantly lower in the BR (+) group than in the BR (−) group (48% vs. 75%, p = .0007). Multivariate analysis revealed that the presence of BR [hazard ratio (HR) = 2.23, 95% confidence interval (CI); 1.48–3.38, p = .0001], lesion length (HR = 1.03, 95%CI; 1.00–1.06, p = .0244), and no scaffold use (HR = 1.58, 95%CI; 1.06–2.36, p = .0246) were predictors of restenosis. The presence of BR is independently associated with clinical outcomes after EVT for de novo calcified femoropopliteal lesions.


Introduction
With the evolution of devices and improvements in techniques, indications for endovascular therapy for femoropopliteal lesions have expanded [1]. However, the clinical outcomes of complex lesions remain unsatisfactory, and EVT for calcified lesions remains challenging. Femoropopliteal lesions with severe calcification negatively affect clinical outcomes, and obtaining procedural success is challenging [2]. There have been many reports of femoropopliteal lesions with severe calcification, and their clinical results have been evaluated using various modalities. Okuno et al. reported that peripheral artery calcification scoring system (PACSS) grade 4 (bilateral wall calcification ≥ 5 cm), which evaluated angiography findings, was independently associated with worse clinical outcomes (poorer patency, increased adverse cardiovascular events, greater target lesion revascularization [TLR], and mortality) [3]. Fujihara et al. reported that when a calcium arc ≥ 180° was found in the lesion on intravascular ultrasound (IVUS), significantly reduced minimum lumen area was, significantly increased stent malapposition, and decreased primary patency were noted [4]. Tokuda et al. reported that a high calcium score evaluated by computed tomography (CT) is related to poor primary patency and increased TLR [5]. Thus, there is no doubt that the severity of calcification worsens clinical outcomes after EVT for femoropopliteal lesions.
Moreover, among the calcifications, light-looking and dark-looking calcifications identified on angiography are often encountered in daily clinical practice. Because there are no reports on the impact of dark-looking calcifications on clinical outcomes, we named it "black rock" (BR). We examined whether BR would affect clinical outcomes after EVT for calcified femoropopliteal lesions.

Patients
This was a retrospective, single-centered, non-randomized study. The flowchart of the study is shown in Fig. 1. A total of 495 patients (677 lesions) were treated for de novo femoropopliteal lesions with calcification between April 2007 and June 2020. Cases in which the contralateral foot was treated (n = 183) and those in which treatment was unsuccessful (n = 23) were excluded. A total of 471 patients (471 lesions) were divided into two groups: those with BR [BR (+) group] and those without BR [BR (−) group]. After performing propensity matching and aligning the background, the clinical results were compared and analyzed. Finally, 119 matched pairs of patients were analyzed. Primary patency and freedom from TLR at 2 years were compared between the two groups. Predictors of restenosis after EVT for de novo calcified lesions were also analyzed. All patients received exercise therapy and medication and had Rutherford class 2-6 symptoms [1]. If angiography or duplex ultrasound showed significant stenosis of the femoropopliteal artery, the vascular team, including vascular surgeons and interventional cardiologists, decided on the applicability of EVT. Follow-up clinical evaluations were performed at least every 6 months using the ankle-brachial index (ABI), duplex ultrasound, contrast-enhanced CT, or angiography.
The study protocol was conducted following the tenets of the Declaration of Helsinki and was approved by the local ethics committee of our hospital. The requirement for informed consent was waived owing to the retrospective study design, in which existing medical records were used. Relevant information regarding the study is available to the public following with ethical guidelines for medical and health research involving human participants.

Intervention
EVTs were performed using an ipsilateral or crossover approach. A 4-to 7-Fr sheath was inserted into the common femoral artery, and 5000 U of heparin was injected. Guidewires measuring 0.014, 0.018, or 0.035 inches were used. The choice of the final device was at the operator's discretion. All patients received dual antiplatelet therapy with aspirin and thienopyridine for at least 1 month. These drugs were administered at least 2 days prior to EVT. Atherectomy devices were not used in this study because they are unavailable in our country.

Fluoroscopy protocol
With each individual in the supine position, lower extremity fluoroscopy was performed for anteroposterior oblique imaging using a digital angiographic system (Allura Xper FD10 systems, Phillips Healthcare, Amsterdam, the Netherlands), and original angiographic images were stored electronically. When the calcification and femur overlapped, the C-arm was rotated such that the calcification and bone did

Definitions
BR was defined as a calcification that measures 1 cm or more in length, occupies more than half of the vessel diameter, and appears darker than the body of the femur on the same screen by angiography (Fig. 2). Procedural success was defined as residual stenosis < 50% without severe vessel dissection. Primary patency was defined as the absence of restenosis or revascularization of the target lesion. Restenosis was defined as a peak systolic velocity ratio of more than 2.4 on duplex ultrasound, > 50% diameter stenosis, or occlusion on follow-up angiography. TLR was defined as the need for revascularization (endovascular or surgical). PACSS was used to categorize the degree of lesion calcification on angiography [3]. The PACSS classifies calcifications into five grades according to laterality and length: grade 0, no visible calcification of the target lesion site; grade 1, unilateral wall calcification < 5 cm; grade 2, unilateral calcification ≥ 5 cm; grade 3, bilateral wall calcification < 5 cm; and grade 4, bilateral calcification ≥ 5 cm. Poor run-off was defined as no or one infra-popliteal vessel [6].

Clinical follow-up
Symptoms, ABI, and duplex ultrasound findings were evaluated every 3 months after treatment. Angiography was performed when duplex ultrasound indicated restenosis.

Statistical analysis
Statistical analysis was performed using the JMP 13 software (SAS Institute Inc., Cary, NC, USA). To avoid the potential effects of a non-randomized study design, a propensity score was calculated using a multivariate logistic regression model, with the presence or absence of BR [BR (+) vs. BR (−)] as the dependent variable. All baseline characteristics [age, sex, hypertension, diabetes mellitus, dyslipidemia, hemodialysis, coronary artery disease, chronic heart failure, arterial fibrillation, smoking, critical limb ischemia, reference vessel diameter (RVD), lesion length, Trans-Atlantic Inter-Society Consensus (TASC) II C or D [1], involving the popliteal artery, poor run-off, PACSS grade, pre-% diameter stenosis (DS), pre-ABI, Crosser use, scoring balloon use, non-compliant balloon use, type of final devices, and IVUS use] were set as covariates. According to the Austin recommendations, a caliper cut-off of 0.20 was used to obtain a satisfactory balance [7]. Continuous variables with normal distributions are presented as mean ± standard deviation and categorical data as frequencies. Continuous variables were examined using the unpaired t-test or Mann-Whitney U test. Categorical variables were compared using the chisquared test. Primary patency and freedom from TLR were analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed to investigate predictors of restenosis. A probability (P) value of < 0.05 was considered statistically significant.

Results
The baseline characteristics of the patients are shown in Table 1. After propensity score matching, 119 pairs of patients were included in this analysis (Table 2). There were no significant differences in baseline clinical data between the two groups in the matched populations. Post-% DS was significantly higher in the BR ( +) group than in the BR ( −) group (25% ± 16% vs. 20% ± 15%, p = 0.0140) (Fig. 3). The 2-year primary patency rate was significantly lower in the BR ( +) group than in the BR ( −) group (45% vs. 74%, p = 0.0005). And the 2-year freedom from TLR was also significantly lower in the BR ( +) group than in the BR ( −) group (65% vs. 81%, p = 0.0422) (Fig. 4a, b).

Discussion
The highlight of the current study is that the primary patency of calcified lesions with BR was significantly lower than that without BR. In addition to BR, lesion length and no scaffold use were associated with loss of the primary patency of femoropopliteal lesions with calcifications. Generally, the higher the calcification score (which considers both area and density of lesion calcification) on CT, the higher the visibility of calcification on angiography; therefore, higher-density calcifications are more likely to be recognized as BR [8][9][10]. Reportedly, the higher the calcification score evaluated using CT, the higher the restenosis rate after revascularization [5,11]. The clinical outcomes of EVT for calcified lesions with BR appear to be poor.
The first reason BR is considered a predictor of restenosis is that sufficient dilatation of the lesion was not achieved. In fact, post%DS was significantly higher in the BR ( +) group. To overcome this, it seems necessary to use devices that can perform lesion modification such as JETSTREAM, orbital atherectomy, SilverHawk/TurboHawk, and lithotripsy balloon etc. [12][13][14][15][16]. Furthermore, it may be effective to use the ARCADIA technique, which involves guidewire passage through the calcified mass and performing balloon dilatation from the inside [17]. In other words, if sufficient vessel dilatation can be obtained by performing lesion modification in some ways, this may improve clinical results. Second, patients with dense calcifications such as BR may have advanced arteriosclerosis. The density of coronary artery calcification is related to coronary heart disease and atherosclerotic cardiovascular disease [18,19]. In summary, the existence of BR itself may be related to its poor clinical outcomes.
In the current study, no scaffold use and lesion length remained predictors of restenosis. In calcified lesions, it is not easy to obtain sufficient dilatation, suppress vessel recoil, and prevent drug penetration. Therefore, it is difficult to expect clinical results even if a drug-coated balloon (DCB) and percutaneous transluminal angioplasty are used [20][21][22]. Fenelli et al. reported that the greater the angle of the calcification arc, the lower the patency after DCB angioplasty [20]. Therefore, it is better to use scaffolds for calcified lesions to achieve primary patency. Additionally, in lesions with BR, lesion expansion is not expected to be sufficient even if a scaffold is used. It may be necessary to  perform lesion modification firmly as described above or to use the "pave-and-crack" technique: a Viabahn stent graft was implanted to "pave" the lesion and protect from vessel rupture, as aggressive predilatation continued until the calcified plaque was "cracked" before lining the entire lesion with a Supera stent [23]. In particular, in long lesions with BR, satisfactory clinical outcomes can hardly be expected, and it can be expressed as a lesion that is not suitable for EVT in the first place. Therefore, surgical reconstruction should be considered [24].

Limitations
The current study has some limitations. First, no atherectomy device was used. Second, the rate of interwoven nitinol stent or stent graft use was very low. Third, the choice of the final device depended on the operator's decision. Finally, the appearance of calcification may differ between facilities.

Conclusion
The presence of BR was independently associated with clinical outcomes after EVT for de novo calcified femoropopliteal lesions.