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Incidence, Risk Factors, and Prognosis of Cholesterol Crystal Embolism Because of Percutaneous Coronary Intervention

Open AccessPublished:January 02, 2022DOI:https://doi.org/10.1016/j.amjcard.2021.11.039
      Cholesterol crystal embolism (CCE) is a rare but serious complication of percutaneous coronary intervention (PCI). However, its incidence, risk factors, and prognosis in the contemporary era are not well known. We included 23,184 patients who underwent PCI in our institution between January 2000 and December 2019 in this study. The diagnosis of CCE was made histologically or by the combination of cutaneous signs and specific blood test results. In patients with CCE, we evaluated the incidence, risk factors, and prognosis. A total of 88 patients (0.38%) were diagnosed with CCE. The incidence of CCE seemed to decline through the investigated 20 years. Positive predictors of CCE were age ≥70 years (68% vs 59%, p = 0.012), aortic aneurysm (23% vs 7.2% p <0.001), and a femoral approach (71% vs 45%, p <0.001), whereas a negative predictor of CCE was the use of an inner sheath (63% vs 77%, p <0.001). The rate of 1-year mortality and the requirement for chronic hemodialysis within 1 year after PCI in patients with CCE were 10% and 11%, respectively. The use of an inner sheath and a nonfemoral approach was associated with a lower incidence of CCE. In conclusion, because the prognosis of patients with CCE is still poor, preprocedural identification of high-risk patients and selection of low-risk procedures could be important for preventing CCE.
      Cholesterol crystal embolism (CCE) is a rare complication that often affects kidneys and lower extremities, causing renal failure and dermatologic manifestations.
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      • Saric M.
      The cholesterol emboli syndrome in atherosclerosis.
      ,
      • Li X
      • Bayliss G
      • Zhuang S.
      Cholesterol crystal embolism and chronic kidney disease.
      CCE is mainly iatrogenic and often associated with intravascular catheter procedures including percutaneous coronary intervention (PCI).
      • Kronzon I
      • Saric M.
      Cholesterol embolization syndrome.
      The incidence of CCE in patients who underwent intravascular procedures including PCI is reported to be 0.6% to 0.9%.
      • Nasser TK
      • Mohler 3rd, ER
      • Wilensky RL
      • Hathaway DR
      Peripheral vascular complications following coronary interventional procedures.
      ,
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      However, data assessing CCE in the contemporary era are scarce. In addition, there are no data that examined the predictors and trends of CCE after PCI in the long term. The prognosis of patients with CCE is poor, with a reported in-hospital mortality of 16%.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      In another study, 47% of patients died of biopsy-proven CCE.
      • Toriu N
      • Sumida K
      • Mizuno H
      • Hasegawa E
      • Suwabe T
      • Kawada M
      • Ueno T
      • Hayami N
      • Sekine A
      • Hiramatsu R
      • Yamanouchi M
      • Hoshino J
      • Sawa N
      • Takaichi K
      • Ohashi K
      • Fujii T
      • Ubara Y.
      Long-term outcome of biopsy-proven cholesterol crystal embolism.
      Previous studies have reported that 33% to 37% of patients with CCE started hemodialysis.
      • Toriu N
      • Sumida K
      • Mizuno H
      • Hasegawa E
      • Suwabe T
      • Kawada M
      • Ueno T
      • Hayami N
      • Sekine A
      • Hiramatsu R
      • Yamanouchi M
      • Hoshino J
      • Sawa N
      • Takaichi K
      • Ohashi K
      • Fujii T
      • Ubara Y.
      Long-term outcome of biopsy-proven cholesterol crystal embolism.
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      • Ravani P
      • Gaggi R
      • Santostefano M
      • Rollino C
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      • Viola BF
      • Maiorca P
      • Venturelli C
      • Bonardelli S
      • Faggiano P
      • Barrett BJ.
      The challenge of diagnosing atheroembolic renal disease: clinical features and prognostic factors.
      Therefore, this study aimed to determine (1) the incidence and trend of CCE after PCI for 20 years; (2) the risk factors for CCE including procedural factors of PCI; and (3) the prognosis of patients with CCE within 1 year after PCI including the requirement for chronic hemodialysis.

      Methods

      A total of 27,416 consecutive patients underwent PCI in our institution between January 1, 2000, and December 31, 2019. After excluding patients who underwent staged PCI within 1 month after PCI since CCE was diagnosed, 23,183 patients were eligible for the analysis. Baseline patient characteristics and clinical, lesion, procedural, and outcome data were collected and compared between patients with and without CCE to determine the incidence, risk factors, and prognosis.
      The loading dose of aspirin (200 mg) and clopidogrel (300 mg) or prasugrel (20 mg) was administered to patients before PCI unless they had previously received antiplatelet therapy. The maintenance dose of aspirin (100 mg) and ticlopidine (200 mg) or clopidogrel (75 mg) or prasugrel (3.75 mg) was administered to patients for at least 1 year after PCI. The addition and discontinuation of other antiplatelet and anticoagulant drugs depended on the attending physician. The approach site, size of a guiding catheter, and technical method also depended on the PCI operator. We have used an inner sheath (Outlook 5Fr Straight; Terumo, Tokyo, Japan) routinely since 2003. The inner sheath has inner and outer diameters of 0.92 and 1.68 mm, with 115 cm in length, and was used in combination with a conventional guiding catheter to reduce the caliber difference between the guiding catheter and the guidewire (Figure 1). The target lesion was then treated by balloon angioplasty to achieve diameter stenosis <30% without significant dissection, and stents including bare-metal stents or drug-eluting stents were used to achieve optimal results in daily practice.
      Figure 1
      Figure 1Caliber difference between guidewires and guiding catheters. (A) with and (B) without an inner sheath. Fr = French.
      CCE was suspected when cutaneous signs such as livedo reticularis, blue toe syndrome, acute kidney injury, and eosinophilia were seen within 30 days after PCI. The definition of CCE is summarized in Table 1, and both probable and definite CCEs were treated equally as CCE in this study. Renal impairment was defined as an increase in serum creatinine more than 0.3 mg/100 ml or 1.5 times or more from baseline, according to Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury (AKI) criteria.
      • Khwaja A.
      KDIGO clinical practice guidelines for acute kidney injury.
      Table 1Definition of cholesterol crystal embolism
      Criterion 1. Histological features such as cholesterol clefts revealed by skin biopsy
      Criterion 2. Cutaneous signs such as livedo reticularis, blue toe syndrome, and digital gangrene
      Criterion 3. Laboratory findings
      a. renal impairment: increase in serum creatinine more than 0.3 mg/100 ml or 1.5 times or more from baseline within 2 weeks after catheterization
      b. eosinophilia: blood eosinophil count more than 500/μL within 4 weeks after catheterization
      Probable cholesterol crystal embolism was defined as the presence of any item in Criteria 2 and 3. Definite cholesterol crystal embolism was defined as the presence of any item in Criterion 1, irrespective of the presence or absence of any item in Criteria 2 and 3.
      Baseline data on the patient, lesion, and procedural characteristics (approach site, size of a guiding catheter, and use of an inner sheath to deliver a guiding catheter) and clinical follow-up data were collected from the hospital charts and telephone interviews with patients or primary care physicians. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, or being treated with antihypertensive agents. Dyslipidemia was defined as having 1 or more of the following: LDL-C ≥140 mg/100 ml, triglycerides ≥150 mg/100 ml, HDL-C ≥40 mg/100 ml or being treated with lipid-lowering agents. Diabetes mellitus was defined as HbA1c ≥6.5% or being treated with oral hypoglycemic agents and/or insulin.
      Categorical variables are expressed as numbers and percentages and compared by the chi-square test. Continuous variables are expressed as mean±standard deviation or median (interquartile range) and compared using the t test or the Wilcoxon rank sum test based on the distribution. Variables that were associated with CCE with a value of p <0.05 in a univariate analysis and those recognized as risk factors from previous studies, acute coronary syndrome (ACS), cerebrovascular disease, and smoking were included in the multivariate models.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      ,
      • Jucgla A
      • Moreso F
      • Muniesa C
      • Moreno A
      • Vidaller A.
      Cholesterol embolism: still an unrecognized entity with a high mortality rate.
      ,
      • Ozkok A.
      Cholesterol-embolization syndrome: current perspectives.
      Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the multiple logistic regression analysis. p values were 2-tailed and those under 0.05 were considered statistically significant in all analyses. Statistical analyses were performed with EZR (Easy R) (Saitama Medical Center, Jichi Medical University, Saitama, Japan) which is a modified version of R commander designed to add statistical functions frequently used in biostatistics for R Software (R Foundation for Statistical Computing, Vienna, Austria).
      • Kanda Y.
      Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics.

      Results

      During the study of 20 years, there were 88 patients (0.38%) with CCE in total, of whom 33 (37.5%) had definite CCE and 55 (62.5%) had probable CCE. The incidence of CCE tended to decrease as years go by (Figure 2).
      Figure 2
      Figure 2The trend of PCI cases and CCE cases from 2000 to 2019. CCE = cholesterol crystal embolism; PCI = percutaneous coronary intervention.
      Clinical and procedural characteristics are summarized in Table 2. Patients with CCE were older and had more abdominal aortic aneurysms and chronic kidney disease as comorbidities than patients without CCE. In patients with CCE, large guiding catheters were more frequently used, an inner sheath was used less, and femoral access was more common than in patients without CCE. Patients with CCE had more lesions with chronic total occlusion and calcification than patients without CCE.
      Table 2Clinical, lesion, and procedural characteristics
      All PatientsCCENon-CCEp Value
      Variables(n = 23,183)(n = 88)(n = 23,095)
      Age (years)69±1173±969±110.012
      Age ≥70 y12,443 (54%)60 (68%)12,383 (54%)0.006
      Women5,613 (24%)21 (24%)5,592 (24%)0.939
      Hypertension16,274 (70%)63 (72%)16,211 (70%)0.775
      Dyslipidemia12,786 (55%)46 (52%)12,740 (55%)0.586
      Diabetes mellitus9,306 (40%)41 (47%)9,265 (40%)0.216
      Family history4,176 (18%)16 (18%)4,160 (18%)0.967
      Smoker14,161 (60%)62 (71%)14,099 (61%)0.071
      AAA1,625 (7.3%)20 (23%)1,605 (7.2%)<0.001
      CKD2,308 (10%)17 (19%)2,291 (10%)0.005
      Hemodialysis1,404 (6.1%)6 (6.8%)1,398 (6.1%)0.779
      ACS8,487 (37%)38 (43%)8,449 (37%)0.206
      Previous PCI10,917(48%)32 (36%)10,885 (48%)0.037
      Previous CABG1,274 (5.4%)7 (8.0%)1,240 (5.4%)0.283
      Femoral approach10,399 (45%)62 (71%)10,337 (45%)<0.001
      Guidewire ≥7 French16,758 (72%)78 (89%)16,680 (72%)<0.001
      Inner sheath17,911 (77%)55 (63%)17,856 (77%)<0.001
      Lesion
      Bifurcation7,272 (33%)20 (25%)7,252 (33%)0.121
      Ostial2,381 (10%)8 (9.1%)2,373 (10%)0.715
      Calcification2,711 (12%)18 (21%)2,693 (12%)0.01
      CTO2,887 (13%)24 (27%)2,863 (12%)<0.001
      Thrombus3,579 (15%)17 (19%)3,562 (15%)0.313
      Lesion Type B2C14,368 (62%)64 (73%)14,304 (62%)0.037
      Debulking device964 (4.2%)6 (6.8%)958 (4.2%)0.213
      Values are n (%) or mean±standard deviation or median (range) unless otherwise specified.
      AAA = abdominal aortic aneurysm; ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CKD = chronic kidney disease; CTO = chronic total occlusion; PCI = percutaneous coronary intervention.
      We included 9 factors with p value <0.05 in a univariate analysis and/or variables considered to be associated with CCE (ACS, cerebrovascular disease, and smoker) in a multivariate logistic regression analysis model to determine the risk factors for CCE (Table 3). Age ≥70 years, abdominal aortic aneurysms, chronic kidney disease, femoral approach, the use of a 7 French or larger guiding catheter, and no use of an inner sheath were univariate predictors of CCE. Age ≥70 years, abdominal aortic aneurysms, smoker, femoral approach, and no use of an inner sheath were significantly associated with CCE, whereas ACS, chronic kidney disease, cerebrovascular disease, and the use of a larger guiding catheter were not independent risk factors for CCE after multivariate analysis.
      Table 3Multivariate analysis of risk factors for cholesterol crystal embolism
      VariablesAll Patients(n = 23,183)CCE(n = 88)Non-CCE(n = 23,095)p ValueOdds Ratio95% Confidence Intervalp Value
      Age ≥70 y12,443 (54%)60 (68%)12,383 (54%)0.0121.891.18–3.010.008
      Acute coronary syndrome8,487 (37%)38 (43%)8,449 (37%)0.2061.080.69–1.690.751
      Abdominal aortic aneurysm1,625 (7.3%)20 (23%)1,605 (7.2%)<0.0013.271.91–5.60<0.001
      Chronic kidney disease2,308 (10%)17 (19%)2,291 (10%)0.0051.590.90–2.830.113
      Cerebrovascular disease2,379 (11%)14 (17%)2,365 (11%)0.1211.120.62–2.020.707
      Smoker14,161 (60%)62 (71%)14,099 (61%)0.0711.681.04–2.700.033
      Femoral Approach10,399 (45%)62 (71%)10,337 (45%)<0.0012.431.41–4.180.001
      Guiding catheter ≥7 French16,758 (72%)78 (89%)16,680 (72%)<0.0011.690.81–3.550.164
      Inner sheath17,911 (77%)55 (63%)17,856 (77%)<0.0010.460.30–0.72<0.001
      Values are n (%).
      CCE = cholesterol crystal embolism.
      In the 88 CCE patients with follow up days of 2,316±1,849 days, 30-day, 1-year, and 5-year mortality rates were 3 (3.4%), 9 (10%), and 25 (28%), respectively. Of the 84 patients whose data on kidney function were available, 9 (11%) patients required chronic hemodialysis within 1 year after PCI.

      Discussion

      The main findings of this study were as follows: (1) The incidence of CCE after PCI was 0.38%, which seemed to have declined through the 20-year study; (2) femoral approach and no use of an inner sheath were associated with a higher incidence of CCE after PCI as procedural factors; (3) patients with CCE may have a poor prognosis.
      Whereas the incidence of clinically evident CCE in real-world practice has been reported to be 0.09% to 2.9%, and CCE was found in 0.31% to 2.4% in autopsy series, the actual incidence and trend of CCE after PCI in the contemporary era are not well known.
      • Kronzon I
      • Saric M.
      Cholesterol embolization syndrome.
      ,
      • Ozkok A.
      Cholesterol-embolization syndrome: current perspectives.
      Fukumoto et al
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      reported in 2003 that CCE was diagnosed in 1.4% of 1786 patients who underwent left-sided cardiac catheterization. In this study, the incidence of CCE in patients who underwent PCI was 0.38%, which was numerically lower than that in Fukumoto et al5’s. The lower incidence in this study could be related to its retrospective study design. However, the definition of CCE was in line with actual clinical practice referred to in previous reports, and this study has a large study population and the advantage of being able to evaluate predictors and trends of CCE.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      ,
      • Toriu N
      • Sumida K
      • Mizuno H
      • Hasegawa E
      • Suwabe T
      • Kawada M
      • Ueno T
      • Hayami N
      • Sekine A
      • Hiramatsu R
      • Yamanouchi M
      • Hoshino J
      • Sawa N
      • Takaichi K
      • Ohashi K
      • Fujii T
      • Ubara Y.
      Long-term outcome of biopsy-proven cholesterol crystal embolism.
      Advanced atherosclerosis and factors contributing to atherosclerosis, for example, ACS, cerebrovascular disease, aortic aneurysm, hypertension, and smoking are proposed as risk factors for CCE after interventional procedures.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      ,
      • Ozkok A.
      Cholesterol-embolization syndrome: current perspectives.
      Whereas some of them were also risk factors of CCE in this study population, interestingly, ACS was not. This may be because PCI procedures for ACS in our institution have dramatically changed during the study period. In particular, the first choice of the approach site has changed from the femoral artery to the radial artery, and there may have been no relation between ACS and CCE because of this transition.
      • Jolly SS
      • Yusuf S
      • Cairns J
      • Niemelä K
      • Xavier D
      • Widimsky P
      • Budaj A
      • Niemelä M
      • Valentin V
      • Lewis BS
      • Avezum A
      • Steg PG
      • Rao SV
      • Gao P
      • Afzal R
      • Joyner CD
      • Chrolavicius S
      • Mehta SR
      RIVAL trial group. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.
      In this study we evaluated the procedural characteristics as risk factors for CCE and the femoral approach was a risk factor of CCE. Fukumoto et al
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      reported that there were no significant differences in the prevalence of femoral approach usage rate between patients with CCE and patients without CCE, and concluded that the ascending thoracic aorta may be the main embolic source, but it is controversial.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      ,
      • Johnson LW
      • Esente P
      • Giambartolomei A
      • Grant WD
      • Loin M
      • Reger MJ
      • Shaw C
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      Peripheral vascular complications of coronary angioplasty by the femoral and brachial techniques.
      • Andò G
      • Cortese B
      • Russo F
      • Rothenbühler M
      • Frigoli E
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      • Briguori C
      • Vranckx P
      • Leonardi S
      • Guiducci V
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      • Investigators Matrix
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      Although Fukumoto et al
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      reported femoral approach as not an independent risk factor for CCE, the complications were seen in 1.59% of 1258 patients treated with a femoral approach and 0.95% of 528 patients treated with other approaches, suggesting that a femoral approach is associated with not a significantly but numerically higher incidence of CCE than other approaches.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      In this study, much more patients who underwent PCI were evaluated for risk factors of CCE after the procedure, thus avoiding a femoral approach to prevent CCE could be recommended for PCI patients. This study has a long study period, during which there was a transition in the major approach site. Because abdominal aortic manipulations are considered to be a risk factor for CCE, the use of the radial artery instead of the femoral artery may prevent CCE.
      • Lin PH
      • Bush RL
      • Conklin BS
      • Chen C
      • Weiss VJ
      • Chaikof EL
      • Lumsden AB.
      Late complication of aortoiliac stent placement- atheroembolization of the lower extremities.
      ,
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      Changing patterns of atheroembolism.
      The procedure of delivering a guiding catheter from the approach site to the coronary artery through the aorta is considered to be related to CCE. We made a hypothesis that the use of a larger guiding catheter would yield a bigger caliber difference between a guiding catheter and a guidewire, with a chance of bringing plaques onto the surface of the aorta wall. The use of an inner sheath would make the caliber difference smaller, which might have prevented plaque from breaking off. A femoral approach is also a risk factor for CCE because the abdominal aorta is 1 of the most heavily involved areas with atherosclerotic plaque. The use of an inner sheath was actually a significant negative predictor of CCE with an OR of 0.46 in our results.
      Whereas a femoral approach was a positive predictor and the use of an inner sheath was a negative predictor of CCE, the size of a guiding catheter was not an independent predictor. When we divided patients into groups by the size of the guiding catheter used, no use of an inner sheath was associated with a higher incidence of CCE in both smaller and larger size guiding catheters. This may be explained by the fact that larger guiding catheters tended to be inserted through the femoral artery, and the approach sites were a true independent risk factor for CCE. Moreover, as depicted in Figure 1, the caliber difference between a guiding catheter and a guidewire was significantly bigger than that between an inner sheath and a guidewire. Compared to that, the difference in the sizes of guiding catheters appears to be very small. Differences in areas with guidewires were 1.92 mm2 for 6Fr guiding catheters and 2.52 mm2 for 7Fr guiding catheters, whereas the difference in the use of an inner sheath was as small as 0.04 mm2 for both sizes of guiding catheters, suggesting that the size of a guiding catheter may not influence the incidence of CCE. To consider the procedural risk factors for CCE after PCI is important because this is the point where we can interfere for prevention.
      The rate of the requirement for chronic hemodialysis within 1 year after PCI was 10.7% in patients with CCE, which was similar to that in a previous report.
      • Toriu N
      • Sumida K
      • Mizuno H
      • Hasegawa E
      • Suwabe T
      • Kawada M
      • Ueno T
      • Hayami N
      • Sekine A
      • Hiramatsu R
      • Yamanouchi M
      • Hoshino J
      • Sawa N
      • Takaichi K
      • Ohashi K
      • Fujii T
      • Ubara Y.
      Long-term outcome of biopsy-proven cholesterol crystal embolism.
      Thirty-day, 1-year, and 5-year mortality rates were 3.4%, 10%, and 28%, respectively for CCE complicated PCI patients, and the early mortality rate was similarly poor to that in a previous study reported as 16% for in-hospital mortality.
      • Fukumoto Y
      • Tsutsui H
      • Tsuchihashi M
      • Masumoto A
      • Takeshita A
      Cholesterol Embolism Study Investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.
      . The importance of prevention can be seen in the fact that the prognosis of patients with CCE is still poor in the last 20 years despite the advances in PCI techniques, devices, and accompanying treatments.
      This study had several important limitations. First, this is a retrospective, observational, single-center study. Second, although we examined all the data from hospital charts as far as possible, the presence of patients with CCE may have been underestimated, because CCE was diagnosed after discharge and some of the patients may have remained unnoticed. Third, there was the possibility of a type II error, especially in the subgroup analysis, because of the limited number of patients with CCE.
      In conclusion, our study confirms that CCE is a complication of PCI with a poor prognosis, even if the procedure is more general nowadays. Avoiding using the femoral approach and using an inner sheath may increase the chance of preventing CCE.

      Disclosures

      The authors have no conflicts of interest to declare.

      Author Contributions

      Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Visualization: Kotaro Takahashi; Data curation: Ayumi Omuro, Masanobu Ohya, Shunsuke Kubo, Takeshi Tada, Hiroyuki Tanaka, Yasushi Fuku; Writing – review and editing; Supervision: Kazushige Kadota.

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