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

Abstract

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 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.1Quinones A Saric M. The cholesterol emboli syndrome in atherosclerosis.Curr Atheroscler Rep. 2013; 15: 315Google Scholar,2Li X Bayliss G Zhuang S. Cholesterol crystal embolism and chronic kidney disease.Int J Mol Sci. 2017; 18: 1120Google Scholar CCE is mainly iatrogenic and often associated with intravascular catheter procedures including percutaneous coronary intervention (PCI).3Kronzon I Saric M. Cholesterol embolization syndrome.Circulation. 2010; 122: 631-641Google Scholar The incidence of CCE in patients who underwent intravascular procedures including PCI is reported to be 0.6% to 0.9%.4Nasser TK Mohler 3rd, ER Wilensky RL Hathaway DR Peripheral vascular complications following coronary interventional procedures.Clin Cardiol. 1995; 18: 609-614Google Scholar,5Fukumoto 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar 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%.5Fukumoto 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar In another study, 47% of patients died of biopsy-proven CCE.6Toriu 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.Clin Exp Nephrol. 2019; 23: 1181-1187Google Scholar Previous studies have reported that 33% to 37% of patients with CCE started hemodialysis.6Toriu 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.Clin Exp Nephrol. 2019; 23: 1181-1187Google Scholar,7Scolari F Ravani P Gaggi R Santostefano M Rollino C Stabellini N Colla L Viola BF Maiorca P Venturelli C Bonardelli S Faggiano P Barrett BJ. The challenge of diagnosing atheroembolic renal disease: clinical features and prognostic factors.Circulation. 2007; 116: 298-304Google Scholar 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. 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. 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.8Khwaja A. KDIGO clinical practice guidelines for acute kidney injury.Nephron Clin Pract. 2012; 120: c179-c184Google ScholarTable 1Definition of cholesterol crystal embolismCriterion 1. Histological features such as cholesterol clefts revealed by skin biopsyCriterion 2. Cutaneous signs such as livedo reticularis, blue toe syndrome, and digital gangreneCriterion 3. Laboratory findingsa. 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 catheterizationb. eosinophilia: blood eosinophil count more than 500/μL within 4 weeks after catheterizationProbable 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. Open table in a new tab 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.5Fukumoto 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar,9Jucgla A Moreso F Muniesa C Moreno A Vidaller A. Cholesterol embolism: still an unrecognized entity with a high mortality rate.J Am Acad Dermatol. 2006; 55: 786-793Google Scholar,10Ozkok A. Cholesterol-embolization syndrome: current perspectives.Vasc Health Risk Manag. 2019; 15: 209-220Google Scholar 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).11Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics.Bone Marrow Transplant. 2013; 48: 452-458Google Scholar 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). 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 characteristicsAll PatientsCCENon-CCEp ValueVariables(n = 23,183)(n = 88)(n = 23,095)Age (years)69±1173±969±110.012Age ≥70 y12,443 (54%)60 (68%)12,383 (54%)0.006Women5,613 (24%)21 (24%)5,592 (24%)0.939Hypertension16,274 (70%)63 (72%)16,211 (70%)0.775Dyslipidemia12,786 (55%)46 (52%)12,740 (55%)0.586Diabetes mellitus9,306 (40%)41 (47%)9,265 (40%)0.216Family history4,176 (18%)16 (18%)4,160 (18%)0.967Smoker14,161 (60%)62 (71%)14,099 (61%)0.071AAA1,625 (7.3%)20 (23%)1,605 (7.2%)<0.001CKD2,308 (10%)17 (19%)2,291 (10%)0.005Hemodialysis1,404 (6.1%)6 (6.8%)1,398 (6.1%)0.779ACS8,487 (37%)38 (43%)8,449 (37%)0.206Previous PCI10,917(48%)32 (36%)10,885 (48%)0.037Previous CABG1,274 (5.4%)7 (8.0%)1,240 (5.4%)0.283Femoral approach10,399 (45%)62 (71%)10,337 (45%)<0.001Guidewire ≥7 French16,758 (72%)78 (89%)16,680 (72%)<0.001Inner sheath17,911 (77%)55 (63%)17,856 (77%)<0.001LesionBifurcation7,272 (33%)20 (25%)7,252 (33%)0.121Ostial2,381 (10%)8 (9.1%)2,373 (10%)0.715Calcification2,711 (12%)18 (21%)2,693 (12%)0.01CTO2,887 (13%)24 (27%)2,863 (12%)<0.001Thrombus3,579 (15%)17 (19%)3,562 (15%)0.313Lesion Type B2C14,368 (62%)64 (73%)14,304 (62%)0.037Debulking device964 (4.2%)6 (6.8%)958 (4.2%)0.213Values 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. Open table in a new tab 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 embolismVariablesAll Patients(n = 23,183)CCE(n = 88)Non-CCE(n = 23,095)p ValueOdds Ratio95% Confidence Intervalp ValueAge ≥70 y12,443 (54%)60 (68%)12,383 (54%)0.0121.891.18–3.010.008Acute coronary syndrome8,487 (37%)38 (43%)8,449 (37%)0.2061.080.69–1.690.751Abdominal aortic aneurysm1,625 (7.3%)20 (23%)1,605 (7.2%)<0.0013.271.91–5.60<0.001Chronic kidney disease2,308 (10%)17 (19%)2,291 (10%)0.0051.590.90–2.830.113Cerebrovascular disease2,379 (11%)14 (17%)2,365 (60%)62 (71%)14,099 (45%)62 (71%)10,337 catheter ≥7 French16,758 (72%)78 (89%)16,680 sheath17,911 (77%)55 (63%)17,856 are n = cholesterol crystal Open table in a new tab Values are n CCE = cholesterol crystal In the 88 CCE patients with days of and mortality were 9 and respectively. the patients data on kidney were 9 patients chronic hemodialysis within 1 year after PCI. The of this study were as (1) The incidence of CCE after PCI was which seemed to have through the (2) femoral approach and no use of an inner sheath were associated with a incidence of CCE after PCI as procedural (3) patients with CCE have a prognosis. the incidence of CCE in practice has reported to be to and CCE was in to in the incidence and trend of CCE after PCI in the contemporary era are not well I Saric M. Cholesterol embolization syndrome.Circulation. 2010; 122: 631-641Google Scholar,10Ozkok A. Cholesterol-embolization syndrome: current perspectives.Vasc Health Risk Manag. 2019; 15: 209-220Google Scholar 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar reported in that CCE was diagnosed in of patients who underwent cardiac In this study, the incidence of CCE in patients who underwent PCI was which was lower than that in The lower incidence in this study could be to its study However, the definition of CCE was in with clinical practice to in previous and this study has a large study and the of being to predictors and trends of 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.J Am Coll Cardiol. 2003; 42: 211-216Google 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.Clin Exp Nephrol. 2019; 23: 1181-1187Google Scholar and factors to for ACS, cerebrovascular disease, aortic and smoking are as risk factors for CCE after interventional 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar,10Ozkok A. Cholesterol-embolization syndrome: current perspectives.Vasc Health Risk Manag. 2019; 15: 209-220Google Scholar of were also risk factors of CCE in this study ACS was be because PCI procedures for ACS in our institution have the study In the of the approach has from the femoral artery to the and there have no between ACS and CCE because of this S J K P A M A P R S femoral access for coronary and intervention in patients with acute coronary a in in Scholar In this study we evaluated the procedural characteristics as risk factors for CCE and the femoral approach was a risk of CCE. 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar reported that there were no significant in the of femoral approach rate between patients with CCE and patients without CCE, and that the be the but is 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.J Am Coll Cardiol. 2003; 42: 211-216Google P A M C Peripheral vascular complications of coronary angioplasty by the femoral and G F M E G C P S F F S F A S G A A F N F F S P M Acute kidney after or femoral access for acute coronary syndrome Am Coll Cardiol. 2017; T J E C A. kidney in patients after cardiac or percutaneous coronary a of and femoral the and Renal 2010; Scholar 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar reported femoral approach as not an independent risk for CCE, the complications were seen in of patients treated with a femoral approach and of patients treated with other that a femoral approach is associated with not a significantly but incidence of CCE than other 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.J Am Coll Cardiol. 2003; 42: 211-216Google Scholar In this study, more patients who underwent PCI were evaluated for risk factors of CCE after the a femoral approach to CCE could be for PCI study has a long study which there was a in the approach abdominal aortic are considered to be a risk for CCE, the use of the artery of the femoral artery RL C complication of of the lower of Scholar The of a guiding catheter from the approach to the coronary artery through the is considered to be to CCE. We made a that the use of a larger guiding catheter a caliber difference between a guiding catheter and a with a of the of the The use of an inner sheath the caliber difference which have from A femoral approach is also a risk for CCE because the abdominal is 1 of the with The use of an inner sheath was a significant negative predictor of CCE with an of in our results. a femoral approach was a predictor and the use of an inner sheath was a negative predictor of CCE, the size of a guiding catheter was not an independent we patients by the size of the guiding catheter used, no use of an inner sheath was associated with a incidence of CCE in both and larger size guiding be by the that larger guiding catheters tended to be through the femoral and the approach were a independent risk for CCE. as in 1, the caliber difference between a guiding catheter and a guidewire was significantly than that between an inner sheath and a to the difference in the of guiding catheters to be in with were for guiding catheters and for guiding whereas the difference in the use of an inner sheath was as as for both of guiding that the size of a guiding catheter not the incidence of CCE. the procedural risk factors for CCE after PCI is important because this is the we for The rate of the requirement for chronic hemodialysis within 1 year after PCI was in patients with CCE, which was to that in a previous 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.Clin Exp Nephrol. 2019; 23: 1181-1187Google Scholar and mortality were and for CCE PCI and the mortality rate was to that in a previous study reported as for in-hospital 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.J Am Coll Cardiol. 2003; 42: 211-216Google The of be seen in the that the prognosis of patients with CCE is still in the 20 years the in PCI and study had important this is a study. we examined all the data from hospital charts as as the presence of patients with CCE have because CCE was diagnosed after and of the patients have there was the of a in the because of the of patients with CCE. In conclusion, our study that CCE is a complication of PCI with a the is more using the femoral approach and using an inner sheath increase the of preventing CCE. The have no of to and

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