Safety and Feasibility of Rotational Atherectomy for Retrograde Recanalization of Chronically Occluded Coronary Arteries

Objective To evaluate the safety and feasibility of rotational atherectomy (RA) in retrograde chronic total occlusion percutaneous coronary intervention (CTO-PCI) by analyzing immediate and long-term outcomes. Background Recent evidence supports the safety and feasibility of RA in CTO-PCI. However, few studies have focused on the use of RA in a retrograde approach to percutaneous revascularization of chronic total occlusion (CTO) lesions and information on long-term outcomes is lacking. Methods A total of 329 patients who underwent retrograde CTO-PCI, out of 1496 consecutive CTO-PCI patients from April 2017 to July 2020, were retrospectively recruited from the 2nd Cardiology Department of the Guangdong Provincial People's Hospital. 16 patients underwent RA (RA group) whilst 313 did not (non-RA group). Results Technical (87.5% vs. 87.5) and procedural (85.9% vs. 87.5) success rates were similar between both groups. There was no difference concerning major procedural complications between groups (12.5% vs. 19.2%; p > 0.75). No in-hospital MACCEs was recorded in the RA group while there were eight MACCEs in the non-RA group (p > 0.99). In the RA group, 2 cases recorded perforation (1 target vessel perforation case and 1 branch vessel perforation), and 55 cases of vessel perforations/dissections were recorded in non-RA group including 18 target vessel perforations, 2 branch vessel perforations, 35 collateral vessel perforations (one patient died from cardiac tamponade). No difference was found in terms of the perforation rate between the two groups (p > 0.99). Over a mean follow-up period of 26.47 ± 14.46 months, use of RA in retrograde CTO-PCI did not result in an increased mortality rate [hazard ratio (HR) 1.58, 95% confidence interval (CI), 0.31–8.21, p = 0.65], major adverse cardiac and cerebral events (HR 0.99, 95% CI 0.35–2.79, p = 0.99) or overall rehospitalization rate (HR 1.27, 95% CI 0.44–3.67, p = 0.67). Adjusted Kaplan–Meier curves according to Cox regression model suggested several predictors influencing the all-cause mortality, cardiovascular mortality, MACCEs, stroke rate, non-fatal myocardial infarction, target vessel recanalization rate and rehospitalization rate in the comparison. Conclusions Our study demonstrates that the in-hospital outcomes and long-term follow up events were the same between RA and non-RA retrograde CTO-PCI patients. RA offered an option for skillful operators in difficult cases when the lesion was severely calcified in retrograde CTO-PCI.

Objective: To evaluate the safety and feasibility of rotational atherectomy (RA) in retrograde chronic total occlusion percutaneous coronary intervention (CTO-PCI) by analyzing immediate and long-term outcomes.
Background: Recent evidence supports the safety and feasibility of RA in CTO-PCI. However, few studies have focused on the use of RA in a retrograde approach to percutaneous revascularization of chronic total occlusion (CTO) lesions and information on long-term outcomes is lacking.
Methods: A total of 329 patients who underwent retrograde CTO-PCI, out of 1496 consecutive CTO-PCI patients from April 2017 to July 2020, were retrospectively recruited from the 2nd Cardiology Department of the Guangdong Provincial People's Hospital. 16 patients underwent RA (RA group) whilst 313 did not (non-RA group).
Results: Technical (87.5% vs. 87.5) and procedural (85.9% vs. 87.5) success rates were similar between both groups. There was no difference concerning major procedural complications between groups (12.5% vs. 19.2%; p > 0.75). No in-hospital MACCEs was recorded in the RA group while there were eight MACCEs in the non-RA group (p > 0.99). In the RA group, 2 cases recorded perforation (1 target vessel perforation case and 1 branch vessel perforation), and 55 cases of vessel perforations/dissections were recorded in non-RA group including 18 target vessel perforations, 2 branch vessel perforations, 35 collateral vessel perforations (one patient died from cardiac tamponade). No difference was found in terms of the perforation rate between the two groups (p > 0.99). Over a mean follow-up period of 26.47 ± 14.46 months, use of RA in retrograde CTO-PCI did not result in an increased mortality rate [hazard ratio (HR) 1.58, 95% confidence interval (CI), 0.31-8.21, p = 0.65], major adverse cardiac and cerebral events (HR 0.99, 95% CI 0.35-2.79, p = 0.99) or overall rehospitalization rate (HR 1.27, 95% CI 0.44-3.67, p = 0.67). Adjusted Kaplan-Meier curves according to Cox regression model suggested several predictors influencing the all-cause mortality, cardiovascular mortality, MACCEs, stroke rate, non-fatal myocardial infarction, target vessel recanalization rate and rehospitalization rate in the comparison.

INTRODUCTION
With advancements in technique and equipment, the success rate of chronic total occlusion percutaneous coronary intervention (CTO-PCI) has greatly improved over the years (1). Despite this, severely calcified coronary artery lesions remain a common cause of failure of equipment delivery and balloon expansion during chronic total occlusion (CTO) recanalization (2)(3)(4)(5)(6). Evidence of the viability and safety of CTO-PCI for calcified lesions using the antegrade approach abounds (7)(8)(9). Reverse controlled antegrade and retrograde subintimal tracking (reverse CART) is the most common retrograde CTO crossing technique in most contemporary series (66% in a multicenter U.S. registry) (10). The use of retrograde crossing techniques, particularly reverse CART, in severely calcified lesions during retrograde CTO-PCI has been considered to confer a relatively high risk of dissection and perforation following subsequent rotational atherectomy (RA) in these lesions. Azzalini et al. proposed the concept of vessel architecture, which sought to distinguish coronary structures (occlusive plaque and adventitia) from the extravascular space, and suggested that CTO-PCI can be carried out safely and effectively as long as one remains within the subadventitial space (11). The feasibility of RA in the subadventitial space during CTO-PCI has been suggested (12,13). The present study sought to further evaluate the safety and feasibility of RA during CTO-PCI using the retrograde approach.

Study Population
In this single-center, retrospective, cohort study, the records of patients who underwent CTO-PCI using the retrograde approach from April 2017 to July 2020 in the 2nd Cardiology Department of Guangdong Provincial People's Hospital were reviewed. The operators performed more than 200 CTO cases per year and with a success rate of about 90%. CTO-PCI was performed on 1496 consecutive patients, of which 329 patients matched the eligibility criteria and were included in our study. RA was used in 16 of the 329 patients because of failure of equipment crossing or balloon undilation in severely calcified stenotic lesions. Figure 1 shows the flow chart of the study population. The eligibility criteria for the study were: (1) age of 18 years or older; (2) an indication for CTO-PCI, including angina symptoms and/or evidence of reversible myocardial ischemia by perfusion imaging or stress testing; and (3) All cases had failed antegrade wire escalation. Patients were excluded if they were older than 85 years or were not the suitable candidates because of severe hemorrhagic disease or intolerance to dual antiplatelet therapy. Demographic, angiographic, procedural, and in-hospital data were obtained from the catheterization laboratory database and hospital charts. Figure 2 demonstrates a case of retrograde CTO-PCI using RA.

Definitions
A coronary CTO was defined as total occlusion of a coronary artery segment with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 and an estimated duration of more than 3 months, with angiographic evidence. The duration of occlusion was estimated according to the onset of clinical symptoms or previous myocardial infarction (MI) with angiographic evidence. The Japanese-CTO (J-CTO) score and PROGRESS-CTO score were used to assess CTO lesions. Werner classification was used to assess collateralization (14)(15)(16). Technical success of retrograde CTO-PCI was defined as residual stenosis <30% and antegrade TIMI flow grade 3. Procedural success was regarded as technical success with no in-hospital major adverse cardiac and cerebral events (MACCEs). In-hospital events were defined as death, periprocedural MI, urgent target vessel revascularization (including repeat PCI or coronary artery bypass graft), pericardiocentesis, cardiac tamponade requiring surgery and stroke. During follow-up, MACCE was defined as cardiovascular death, non-fatal MI, ischemia-driven target vessel recanalization and stroke. The criteria for MI were based on the new Fourth Universal Definition of MI (17). Stent thrombosis was defined in accordance with the Academic Research Council criteria (18).

Interventional Procedures
Before and after CTO-PCI, all patients received optimal dual antiplatelet therapy (aspirin 100 mg once daily and clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily). Patients received an initial bolus of intravenous unfractionated heparin (150 IU/kg) during the procedure; additional boluses were given to maintain an activated clotting time (ACT) >300 s, which was monitored every 30 min. At the operator's discretion, additional doses of a glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor were administered selectively. The choice of vascular access depended on the operator's personal preference as well as anatomical considerations. Retrograde recanalization techniques and equipment were used at the operator's discretion. RA was used following failure of balloon crossing or expansion, or after balloon rupture or failure of other equipment to cross after wire externalization. Rota wire R (Boston Scientific Corp) was exchanged after the extraction of wires via a Finecross R microcatheter (Terumo Company, Japan) or Corsair R (Asahi  Intec, Japan) microcatheter. If the microcatheter failed to cross, Rota wire R was manipulated to primarily cross the CTO lesion (19). Retrograde angiography was performed to ensure that the Rota wire was in the true lumen. The size of the burr used was at the discretion of the operator. The rotational speed of RA was between 160000 and 200000 rotations per minute (RPM). Balloon pre-dilatation was performed after successful RA, followed by drug eluting stent implantation.

Follow-Up
Follow-up data was collected by telephonic interviews years after PCI as well as through the revision of clinical documentation when patients returned for further consultation. All data collection and use of patient data were done in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Guangdong Provincial people's hospital and Guangdong Academy of Medical Sciences [No. GDREC2017196H(R1)] in July 2017.

Statistical Analysis
Quantitative data are reported as means ± SD and tested by the Student t-test. Pearson χ2 test or Fisher's exact test was used to analyze differences in qualitative data for discrete variables. The Kaplan-Meier method was used to calculate and graphically describe the free rates of MACCE, MI, stroke, survival, and rehospitalization of the two groups. The multivariable Cox regression analysis model was built by stepwise selection. All baseline and procedural patient variables in univariable analysis defined by p < 0.1 were entered into the stepwise model. Differences with a p < 0.05 were regarded as statistically significant. All statistical analyses were performed using the SPSS software package, version 20.0 (SPSS Inc, Chicago, IL) and GraphPad Prism version 9 (GraphPad Software Inc., San Diego, CA, USA).

Baseline Clinical Characteristics
A total of 329 patients who fulfilled the inclusion criteria were included in the study. Clinical characteristics of the study population are shown in Table 1. Sixteen patients underwent RA during retrograde CTO-PCI while 313 patients had retrograde CTO-PCI without RA. The distribution of clinical characteristics between the two groups was not different. The mean age was 59.70 ± 10.52 years in the non-RA group and 60.87 ± 9.82 in the RA group, and more than 90% were male in both groups. There were no differences in the prevalence of hypertension, hyperlipidemia, smoking, diabetes mellitus or history of prior PCI or coronary artery bypass graft between the two groups. Renal function and ejection fraction did not differ significantly between the two groups.

Angiographic Characteristics
The angiographic characteristics of the patients' coronary lesions are described in   Table 3 showed the procedural characteristics of the two groups. There was a higher trend toward use of reverse CART in successful crossing strategy (75% in RA vs. 59.4% in non-RA; p = 0.29), and retrograde wire escalation tended to be lower in RA patients (18.8% vs. 27.2%; p = 0.57). In the RA group guide catheter extension (Guidezilla TM , Boston Scientific, Natick, USA) was more frequently applied, as compared with non-RA subjects (75% vs. 46%, p = 0.04). IVUS use was not different in cases of both cohorts. Septal collateral channel was the common interventional collateral channel in both retrograde PCI groups and showed no significant difference. Epicardial collateral channel tended to be applied more often in non-RA group (18.8% vs. 25.6%; p = 0.77). There was no significant difference in the number and length of stents implanted between the two groups. The main indications for RA during retrograde CTO-PCI were failure of equipment to cross the lesion (68.8%), followed by failure of balloon expansion in 25%, and balloon rupture in 6.3% of the procedures. In most cases, one burr was enough for RA (87.5%), and two burrs were used in 12.5%. The largest burr size was 1.25 mm in 37.5% and 1.50 mm in 62.5%. The mean rotational speed for RA was 186,363 ± 12,863 RPM. There was no Rota wire uncrossing in our center and rotational atherectomy

Procedural Complications and In-hospital Outcomes
Procedural complications and in-hospital outcomes were shown in Table 4. There was no difference concerning major procedural

DISCUSSION
To the best of our knowledge, this is the first study to compare the outcomes (in-hospital and long-term) of the use of RA in CTO-PCI using the retrograde approach. One of the main findings of our study was that the procedural success rate of retrograde CTO PCI was similar whether or not RA was performed. Additionally, we found that thought RA was used more often in patients with extreme vessel tortuosity and calcification, cases in both RA and non-RA groups performing retrograde CTO PCI were multivessel disease, multi-CTO lesions, and complex lesions (evidenced by J-CTO score and PROGRESS-CTO score) which can be regarded as CHIP (Complete Revascularization for High Risk Indicated Patients Session). We found similar rates of in-hospital complications as well as long-term survival, stroke, MI and MACCE rates with or without the use of RA during retrograde CTO-PCI despite similar rates of use of reverse-CART in the two groups. The rehospitalization rate was not higher when RA was used.
Balloon un-crossable or un-dilatable lesions account for 9 and 2% of CTO-PCI failure, respectively (20). Strategies such as the buddy wire technique, deep intubation of the guiding catheter, and the mother-and-child guide catheter techniques are frequently employed to facilitate device advancement during the procedure. RA can be very useful in this setting by debulking lesions with severe calcification to improve vascular compliance and device trafficability. A recent multicentral study suggested that excimer laser coronary atherectomy was effective in uncrossable CTO lesions (21). Although there is a lack of sufficient practice, we are optimistic about its prospects.
Recent randomized controlled trials have suggested that RA for complex calcified lesions was similar to that of plain old balloon angioplasty with regards to long-term clinical outcomes or reduction in lumen loss (4,22,23). Abdel-Wahab et al. have reported similar rates of immediate and 9-month lumen loss when modified balloons or RA were used in severely calcified coronary lesions (5). However, a recent post hoc analysis of the PREPARE-CALC (The Comparison of Strategies to PREPARE Severely CALCified Coronary Lesions) randomized trial found that RA had a higher procedural success rate compared with modified balloons in non-left anterior descending artery lesions (24). A retrospective review of 3540 patients in 21 centers (part of the PROGRESS-CTO registry) identified 116 patients in whom RA was performed and 3424 patients without RA, using both the antegrade and retrograde approaches to CTO-PCI (7). In this study, the technical and procedural success rates and MACCE rates were similar between the groups. RA was used in only 4.9% of patients undergoing retrograde CTO-PCI in our center, similar to the rate in the PROGRESS-CTO registry. This indicates that whilst RA is not a necessity in CTO-PCI, it nevertheless remains an effective and useful option in the occasional resistant lesion. A small study (n = 285) suggested a trend toward a lower 1-year MACCE rate when RA was used in resistant CTO lesions, but this advantage was lost after adjusting for confounding variables on multivariate Cox regression analysis (HR 1.25, 95% CI, 0.33-1.94, p = 0.242) (9). Similar to our study, a single-center study in Germany that enrolled CTO (n = 75) and non-CTO (n = 317) PCI patients who had RA prior to stent implantation found no differences in in-hospital MACCE rates despite the occurrence of significantly more dissections when RA was employed (8). In an in-hospital cohort of 129 patients undergoing CTO-PCI with RA reported a higher incidence of dissection in the retrograde arm compared with the antegrade approach (25).
In this study, the technical success rate of RA procedural was 100%, which we attribute, amongst other things, to the good support afforded by 7F guiding catheters and guide catheter-extensions (Guidezilla TM ), as necessary, through unilateral radial and femoral artery or bilateral femoral artery vascular access sites. We analyzed the access site of the two groups and the result suggesting that in retrograde CTO-PCI surgery operators tended to apply right radial plus femoral artery. Comparing with bilateral radial artery and bilateral femoral artery, this method could provide a stronger support for catheters with less puncture complications and restriction after surgery (26). The right access is more feasible for the operators to stand a long time in the operation. For those lesions with severe tortuosity and calcification, the microcatheter often failed to cross in the antegrade approach (to facilitate wire exchange). In these cases, sophisticated operators would trace the track left by the stiff wire in the calcified lesion with Rotawire in the antegrade microcatheter and return to the distal true lumen. As the lesion was usually severely calcified, a track was usually left in the lesion without elastic recoil (19). During this procedure, retrograde angiography was performed once the Rotawire crossed the lesion to ensure that it was in the true lumen to reduce the risk of perforation (12). The smallest-sized burr (1.25 mm) was used at a speed of 160,000-180,000 RPM. In our study, reverse CART was used significantly more frequently in the RA group. As the lesions in the RA group were longer and more calcified, antegrade CTO wires were more prone to cross into the subadventitial space with inability to return to the true lumen (11). In this scenario, we switched over to the retrograde approach for recanalization, which likely accounted for the more frequent use of reverse CART in the RA group. Reverse CART allows the guide wire to travel through the subadventitial space and could lead to extension of the dissection plane and predisposition to perforation. This was confirmed by the findings of our study. However, we also found that the technical success, long term MACCE, and survival rates were similar, independent of the use of RA (27). Guidezilla TM usage was higher in the RA group due to more severe calcification and tortuosity of the target vessels. Deep intubation of the Guidezilla TM helped to direct the retrograde guide wire following CTO crossing (28). After successful retrograde wire externalization, the burr was delivered for RA. During the procedure, the Guidezilla TM provided stability, maintained coaxiality with the Rotawire, and protected proximal branches during RA in distal lesions.
We found two cases regarded as procedural failure. Both two cases were due to vessel perforation and needed endovascular coiling to arrest the bleed. One of the two cases of perforation developed into pericardial tamponade requiring pericardial drainage. None of the two patients experienced adverse cardiovascular or cerebral events. Historically, a feared complication of RA has been enlargement of a subintimal dissection. We used reverse CART and wire knuckle techniques for retrograde CTO lesion crossing. This study found two cases of dissection in the RA group, but was not significantly higher than the rate recorded in the non-RA group. Research suggests that low-speed (140,000 RPM) RA did not result in a reduction in the slow flow phenomenon compared with high-speed (190,000 RPM) RA (29). But one successful case in the RA group reported cardiac death during rehospitalization. Overall, procedural success and MACCE rates were not different between the two groups in-hospital and during follow up.
Our study had some limitations. First, as a singlecenter retrospective study, the lack of randomization and potential for selection bias during the procedure might have affected the study outcomes. Second, the operations were performed by skillful operators in a large center and may not applicable to those small centers. Additionally, the number of patients who underwent RA during retrograde CTO-PCI was relatively small. Follow-up angiography was not performed for our patients. In this retrospective study, economic considerations in the past may lower the usage rate of IVUS, but our practice suggested that IVUS was a vital approach in the RA procedure for e.g., the selection of burr and RA guidewire, prevention of coronary perforation, evaluation of RA, and selection of the stent (30). IVUS was applied in complicating CTO lesions if possible. As a result, the true benefits of RA in CTO-PCI using the retrograde approach need to be further assessed by larger studies or dedicated randomized trials.

CONCLUSION
In summary, our study demonstrates that the in-hospital outcomes and long-term follow up events were the same between RA and non-RA retrograde CTO-PCI patients. RA offered an option for skillful operators in difficult cases when the lesion was severely calcified in retrograde CTO-PCI.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.