Original research 469
Preprocedural red blood cell distribution width predicts bare metal stent restenosis Abdulmelik Yıldıza, Fatih Tekinera, Ahmet Karakurtc, Gokce Sirina and Dursun Dumanb Background It has been shown that increased red blood cell distribution width (RDW) predicts adverse outcomes in cardiovascular disease and in patients undergoing a percutaneous coronary intervention. The aim of the present study was to assess the predictive value of preinterventional RDW on the development of in-stent restenosis (ISR) in patients undergoing stent implantation. Materials and methods In this retrospective study, we compared 131 patients with ISR and 138 patients without ISR who had undergone bare metal stent implantation. Results Preprocedural RDW was significantly higher in patients with ISR than those without restenosis (14.6±3.2 vs. 13.4±1.6%, P < 0.001). Stent length was significantly longer in patients with than those without restenosis (17.9±5.6 vs. 16.2±5.2 mm, respectively, P = 0.03). Compared with patients with restenosis, patients without restenosis had a lower rate of diabetes (28 vs. 61 patients, P = 0.001), a significantly short period between two coronary angiographies (9.8±9.3 vs. 12.9±11.6 months, respectively, P = 0.02), and lower triglyceride levels (133±53 vs. 198±121 mg/dl, respectively, P = 0.05).
Introduction Red blood cell distribution width (RDW), a measure of the variability in the size of circulating erythrocytes, is a component of the complete blood count. RDW independently predicts mortality in cardiovascular disease and in patients undergoing percutaneous coronary intervention (PCI) [1–5]. It is postulated that inflammation, malnutrition, older age, and underlying renal dysfunction may increase RDW, which is highly associated with increased cardiovascular morbidity and mortality [6–8]. Previous reports reported a significant correlation between RDW and C-reactive protein (CRP), an inflammatory marker, in cardiovascular disease [9]. Despite major advances in interventional techniques and drug therapies, in-stent restenosis (ISR) remains a serious complication in interventional cardiology [10]. It occurs in up to 30% of patients treated with a bare metal stent (BMS) [11]. The inflammatory process plays an important role not only in the initiation and progression of atherosclerosis [12], but also in the development of stent restenosis [13,14]. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
In multivariate logistic regression analysis, diabetes mellitus, stent length, preprocedural RDW, and current smoking independently predicted ISR. Conclusion Increased preinterventional RDW significantly predicts bare metal stent restenosis and might represent a useful screening tool to stratify patients according to a higher or a lower risk of ISR after stent implantation in patients with stable and unstable angina c 2014 Wolters pectoris. Coron Artery Dis 25:469–473 Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:469–473 Keywords: coronary artery disease, percutaneous coronary intervention, red blood cell distribution width, stent restenosis a Department of Cardiology, Medical Park Hospital, bDepartment of Cardiology, School of Medicine, Istanbul Medipol University, Istanbul and cDepartment of Cardiology, School of Medicine, Kafkas University, Kars, Turkey
Correspondence to Dursun Duman, MD, Istanbul Medipol Hospital, Kosuyolu/Kadikoy, Istanbul 34718, Turkey Tel: + 90 216 544 6666; fax: + 90 216 545 2006; e-mail: [email protected] Received 2 January 2014 Revised 29 January 2014 Accepted 11 February 2014
This study tested the hypothesis suggesting that the preprocedural RDW predicts ISR in BMS in patients with stable and unstable angina pectoris.
Materials and methods We assessed clinical and angiographic data of the patients with normal renal function (serum creatinine < 1.3 mg/dl) who had undergone successful stent implantation from January 2008 through June 2013 at our institution. Only patients with stable and unstable angina who had undergone BMS implantation were included. The local ethics committee approved the study. Patients with unstable angina pectoris were defined according to the Braunwald classification [15]. As part of our preprocedural protocol, complete blood count and peripheral differentials had already been available before coronary angiography for all patients. Patients’ clinical and demographic characteristics including age, sex, coronary artery disease risk factors (arterial hypertension, diabetes mellitus, smoking, family history DOI: 10.1097/MCA.0000000000000105
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470 Coronary Artery Disease 2014, Vol 25 No 6
of coronary artery disease, dyslipidemia), creatinine, medications, and left ventricular ejection fraction were recorded. Coronary interventions were performed according to current practice guidelines and recorded in digital storage for quantitative analysis. Degree of coronary stenosis was estimated visually by experienced interventional cardiologists. A luminal narrowing 50% in a major subepicardial vessel (left anterior descending, left circumflex, or right coronary artery) was defined as significant stenosis. Target lesions were treated by elective PCI with coronary stent implantation. All patients received BMS. Direct stenting was applied as possible, but if indicated, balloon predilatation was performed before stent implantation, and if the primary angiographic result was not satisfactory, postdilatation was used. All patients received clopidogrel 600 mg at least 6 h before the stent implantation. Patients received weight-adjusted intravenous heparin before the intervention. Procedural success was defined as reduction of stenosis to less than 10% residual narrowing, with improvement in ischemic symptoms and without major procedure-related complications: death, emergency bypass surgery, or myocardial infarction (defined as greater than two times increase in creatine kinase-MB levels) [16]. ISR was defined as restenosis at the site of the stented lesion within 5 mm proximal or distal to the stent edges (in segment), with greater than 50% narrowing of the lumen diameter according to the results of control coronary angiographies [17]. Aspirin (100 mg/day) was administered indefinitely; clopidogrel 75 mg daily was continued for at least 6 months after the intervention. For patients’ data, we gained access retrospectively to the data at the time of interest when the patients with normal renal function underwent coronary stent implantation and then control coronary angiography was performed because of anginal symptoms and positive treadmill test results, thus recalling clinical, angiographic, and laboratory characteristics at that time. As such, we were able to collect the data for 663 patients. Patients were excluded from analysis if they had undergone drugeluting stent implantation (n = 221), had hemoglobin level less than 12 g/dl (n = 158), and had clinical evidence of cancer (n = 5), chronic inflammatory disease (n = 2), or any active infectious disease (n = 8), leaving 269 patients to be included in the study. Intraobserver and interobserver variabilities of stent restenosis analysis were assessed in a subset of 50 patients. Interpretations of the two investigators on the presence or absence of ISR agreed in 92% (62 of 71) and 96% (67 of 71), respectively. Intraobserver variability was assessed by one investigator. The two readings were concordant for the presence or absence of ISR in 95% (66 of 72) and 96% (67 of 71), respectively.
Hematological parameters, including hemoglobin, RDW, and platelet count, were analyzed by Cell-Dyn 3700 (Abbott Laboratories, Abbott Park, Illinois, USA).
Statistical analysis
Continuous variables are expressed as mean±SD. Categorical variables are expressed as percentages. To compare parametric continuous variables, Student’s t-test was used; to compare nonparametric continuous variables, the Mann–Whitney U-test was used; and to compare categorical variables, the w2-test was used. Multivariate logistic regression analysis was used to identify the independent predictor of ISR. All variables showing significance values less than 0.05 on univariate analysis (current smoking, diabetes mellitus, stent length, preprocedural RDW, period between two coronary angiographies) were included in this model. Two-tailed P values less than 0.05 were considered significant and the confidence interval was 95%. All statistical studies were carried out using the SPSS program (version 15.0; SPSS Inc., Chicago, Illinois, USA).
Results In the study population, mean age was 62±11 years; clinical and procedural data of the population according to with ISR and without ISR (n = 131 and 138, respectively) are presented in Table 1. There were no significant differences in sex, age, medications, hemoglobin, and platelet levels, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol, and left ventricular ejection fraction between the 138 patients without ISR and the 131 patients with ISR. The lesion characteristics and angioplasty procedural variables were identical in both patient groups, except for stent length. Stent length was significantly longer in patients with than those without restenosis (17.9±5.6 vs. 16.2±5.2 mm, respectively, P = 0.03). Compared with patients with restenosis, patients without restenosis had a significantly short period between two coronary angiographies (9.8±9.3 vs. 12.9±11.6 months, respectively, P = 0.02) and lower triglyceride levels (133±53 vs. 168±121 mg/dl, respectively, P = 0.05) (Table 1). Patients with ISR were more diabetic and had higher smoking rates (61 vs. 28 patients, P = 0.001, and 58 vs. 44 patients, P = 0.04). Preprocedural RDW was significantly higher in patients with ISR than those without restenosis (14.6±3.2 vs. 13.4±1.6%, P < 0.001). If RDW was included in univariate analysis as a qualitative variable, RDW levels of at least 13.0% were also associated with increased ISR (P < 0.001). CRP levels were similar between the two groups. However, in subgroup analysis, CRP levels were significantly higher in the unstable angina group and associated with increased ISR in this subgroup (3.1±2.4 vs. 2.1±2.2 mg/l, P = 0.03).
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Prediction of stent restenosis Yıldız et al. 471
Table 1
Variables of the patients with in-stent restenosis versus without in-stent restenosis With ISR (n = 131)
Without ISR (n = 138)
103 (79) 61.9±11.0 65.8±8.2 58 (44) 45 (34) 61 (46) 76 (58)
100 (73) 61.3±10.7 63.5±8.6 44 (32) 51 (37) 28 (20) 75 (54)
0.67 0.51 0.72 0.04 0.38 0.001 0.62
61 (47) 70 (53) 1.79±0.80 45 (34)
77 (56) 61 (44) 1.64±0.72 44 (32)
0.11 0.14 0.07 0.38
78 (59) 34 (26) 45 (34) 17.9±5.6 3.09±0.64
73 (53) 45 (33) 43 (31) 16.2±5.2 3.20±0.70
0.21 0.14 0.33 0.03 0.08
39 (30) 78 (68) 19 (15) 69 (53) 79 (60) 14.6±3.2 96±10 42±13 135±64 168±121 13.6±1.9 242±70 0.87±0.25 2.4±2.3 9.8±9.3
50 (36) 71 (51) 21 (15) 71 (51) 44 (32) 13.4±1.6 89±13 40±10 123±31 133±53 14.1±1.6 254±80 0.88±0.22 2.1±2.1 12.9±11.6
0.16 0.18 0.36 0.14 < 0.001 < 0.001 0.71 0.40 0.27 0.05 0.11 0.21 0.91 0.23 0.02
Male sex [n (%)] Age (years) LVEF (%) Current smoker [n (%)] Family history of CAD [n (%)] Diabetes mellitus [n (%)] Hypertension [n (%)] Cause of stent implantation [n (%)] Stable angina pectoris Unstable angina pectoris Number of significantly diseased vessels/patients Multivessel intervention [n (%)] Coronary vessel treated [n (%)] Left anterior descending Circumflex Right Stent length (mm) Stent diameter (mm) In hospital medical treatment [n (%)] ACE-I/ARB b-Blocker Ca-canal blocker Statins RDW Z 13.0% [n (%)] RDW (%) Fasting glucose (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Hemoglobin (g/l) Platelet count (109/l) Creatinine (mg/dl) C-reactive protein (mg/l) Period between two coronary angiographies (months)
P
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; ISR, in-stent restenosis; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; RDW, red blood cell distribution width.
Multivariate logistic regression analysis according to the risk of in-stent restenosis
Table 2
Number of significantly diseased vessels/patients Period between two coronary angiographies Current smoker Stent segment length Diabetes mellitus RDW
OR
95% CI
P
1.4 0.98 1.24 1.08 1.19 1.4
0.99–1.98 0.95–1.98 0.32–0.97 1.03–1.13 0.26–0.77 1.18–1.67
0.06 0.09 0.04 0.007 0.004 0.001
CI, confidence interval; OR, odds ratio; RDW, red blood cell distribution width.
In multivariate logistic regression analysis, diabetes mellitus, stent length, preprocedural RDW, and current smoking independently predicted ISR (Table 2).
Discussion The results of this study show that preinterventional RDW levels independently predict BMS restenosis in patients with stable and unstable angina. In previous studies, the prognostic significance of RDW in various cardiovascular disease has been shown; the present study shows for the first time the close relationship between RDW and BMS restenosis [1–8]. In recent years, studies have consistently shown that RDW is closely related to the prognosis and long-term
adverse events of cardiovascular diseases [6–8]. The underlying mechanism of the relationship between high levels of RDW and cardiovascular disease is unclear. Inflammation plays an important role in the atherosclerotic process [18]. Inflammatory cytokines have been found to suppress the erythrocyte maturation; thus, juvenile erythrocytes enter into circulation [19]. In addition, elevated levels of neurohumoral mediators stimulate erythropoiesis, for example, angiotensin II may affect the erythroid progenitor cells with a direct stimulation [20]. These factors may increase the variability in circulation red cell sizes. The investigators showed a relationship between generalized inflammation and elevated levels of RDW and found an association of RDW with high-sensitive CRP and erythrocyte sedimentation rate, which are indicators of inflammation [21]. Previous studies have suggested that ISR was associated with increased levels of CRP, interleukin-6, and serum amyloid A protein before or after the procedure [22–25]. They also reported that the preprocedural CRP values appeared to be a powerful predictor of both early and late restenosis in patients undergoing coronary angioplasty and stent implantation [26–29]. Buffon et al. [26] showed a significant association between CRP and restenosis. Clinical restenosis developed in 63% of patients with high
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CRP levels and in 27% of those with normal CRP levels. Walter et al. [28] reported that patients with increased CRP levels had a significantly higher risk of ISR with a rate of 19% in the lowest tertile compared with 37 and 45% in the upper tertiles, respectively. In contrast to these findings, other studies did not show the predictive value of inflammatory markers on ISR. Dibra et al. [29] and Delhaye et al. [30] showed that angiographic ISR was observed at similar rates in patients with elevated CRP levels compared with patients with normal levels. In the present study, our results suggested that preprocedural CRP levels did not predict clinical restenosis. However, in subgroup analysis, CRP levels were significantly higher in the unstable angina group and associated with ISR. Differences in the pathobiology between stable and unstable coronary syndromes and the widespread use of statins with anti-inflammatory and pleitrophic activity in our cohort of patients most likely explain our findings. In a recent study, Turak et al. [31] showed that a high preprocedural neutrophil-to-lymphocyte ratio significantly predicts BMS restenosis in patients with stable and unstable angina pectoris. In the present study, we did not assess the neutrophil : lymphocyte ratio as a marker of restenosis. Although the present study confirms the predictive role of known risk factors for restenosis, such as diabetes mellitus and stent length, it also shows a strong association between RDW and ISR, which has not been reported before. RDW remained a strong independent predictor of ISR even after adjustment for all other risk factors in multivariate analysis. Only hemoglobin levels were measured in this study. Iron levels, vitamin B12, and folate, which may affect RDW levels, were not measured. However, we did not enroll patients with anemia in our study. We believe that this makes it highly unlikely that the predictive value of RDW was related to iron deficiency. Furthermore, the incidence of clinically significant vitamin B12 and folate deficiency is low in a modern population. In a large-scale study, it was found that RDW was an independent predictor of mortality and the investigators concluded that the relationship between RDW and mortality was not confounded by anemia-related deficiencies such as vitamin B12, folate, and iron [32]. In previous studies, the restenosis rates reported within 6 months in patients with BMS ranged between 16 and 44% [33,34]. However, in the present study, our results suggested that BMS restenosis developed in 131 patients (48.7%). We followed up the patients with BMS 9.8±9.3 months. In agreement with our study, Mohan and Dhall [35] reported that BMS restenosis was 48.8% 6–9 months after the interventional procedure. Therefore, the higher stent restenosis rate may be related to the longer follow-up period. In addition, previous studies
have shown that exercise-induced angina at follow-up and a positive exercise treadmill test independently predict restenosis [36]. A pooled analysis of 15 treadmill studies involving 2250 patients with angiographic follow-up showed a 50% positive predictive value and a 76% negative predictive value for the exercise treadmill test [37–41]. In our study, control coronary angiography was performed in patients who had anginal symptoms and positive treadmill test results. We did not perform routine coronary angiography in all stented patients. Therefore, the high restenosis rate in the present study may be related to this factor. Another factor that may have led to overestimation of coronary stenosis in our population was the method of assessment of stenosis. We used visual interpretation instead of qualitative coronary angiography, which allows more accurate estimation of coronary artery stenosis. In a recent study, Nallamothu et al. [42] showed that physicians tended to assess coronary lesions treated with PCI as more severe than measurements by qualitative coronary angiography. Limitations
Our study was carried out on a retrospective basis and represented a single-center experience. The definition of stenosis was based on visual assessments, not on quantitative measurements. Before a procedure, a single blood sample does not anticipate the persistence of RDW over time. The second limitation is that the study was carried out in terms of BMS, and thus these results cannot be directly extrapolated to patients receiving drug-eluting stents. Conclusion
The present study confirms that preinterventional RDW predicts the risk of BMS restenosis in patients with stable and unstable angina pectoris, and may represent a useful screening tool to stratify patients according to the risk of future ISR after stent implantation and may influence clinical management.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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Preprocedural red blood cell distribution width predicts bare metal stent restenosis Abdulmelik Yıldıza, Fatih Tekinera, Ahmet Karakurtc, Gokce Sirina and Dursun Dumanb Background It has been shown that increased red blood cell distribution width (RDW) predicts adverse outcomes in cardiovascular disease and in patients undergoing a percutaneous coronary intervention. The aim of the present study was to assess the predictive value of preinterventional RDW on the development of in-stent restenosis (ISR) in patients undergoing stent implantation. Materials and methods In this retrospective study, we compared 131 patients with ISR and 138 patients without ISR who had undergone bare metal stent implantation. Results Preprocedural RDW was significantly higher in patients with ISR than those without restenosis (14.6±3.2 vs. 13.4±1.6%, P < 0.001). Stent length was significantly longer in patients with than those without restenosis (17.9±5.6 vs. 16.2±5.2 mm, respectively, P = 0.03). Compared with patients with restenosis, patients without restenosis had a lower rate of diabetes (28 vs. 61 patients, P = 0.001), a significantly short period between two coronary angiographies (9.8±9.3 vs. 12.9±11.6 months, respectively, P = 0.02), and lower triglyceride levels (133±53 vs. 198±121 mg/dl, respectively, P = 0.05).
Introduction Red blood cell distribution width (RDW), a measure of the variability in the size of circulating erythrocytes, is a component of the complete blood count. RDW independently predicts mortality in cardiovascular disease and in patients undergoing percutaneous coronary intervention (PCI) [1–5]. It is postulated that inflammation, malnutrition, older age, and underlying renal dysfunction may increase RDW, which is highly associated with increased cardiovascular morbidity and mortality [6–8]. Previous reports reported a significant correlation between RDW and C-reactive protein (CRP), an inflammatory marker, in cardiovascular disease [9]. Despite major advances in interventional techniques and drug therapies, in-stent restenosis (ISR) remains a serious complication in interventional cardiology [10]. It occurs in up to 30% of patients treated with a bare metal stent (BMS) [11]. The inflammatory process plays an important role not only in the initiation and progression of atherosclerosis [12], but also in the development of stent restenosis [13,14]. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-6928
In multivariate logistic regression analysis, diabetes mellitus, stent length, preprocedural RDW, and current smoking independently predicted ISR. Conclusion Increased preinterventional RDW significantly predicts bare metal stent restenosis and might represent a useful screening tool to stratify patients according to a higher or a lower risk of ISR after stent implantation in patients with stable and unstable angina c 2014 Wolters pectoris. Coron Artery Dis 25:469–473 Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:469–473 Keywords: coronary artery disease, percutaneous coronary intervention, red blood cell distribution width, stent restenosis a Department of Cardiology, Medical Park Hospital, bDepartment of Cardiology, School of Medicine, Istanbul Medipol University, Istanbul and cDepartment of Cardiology, School of Medicine, Kafkas University, Kars, Turkey
Correspondence to Dursun Duman, MD, Istanbul Medipol Hospital, Kosuyolu/Kadikoy, Istanbul 34718, Turkey Tel: + 90 216 544 6666; fax: + 90 216 545 2006; e-mail: [email protected] Received 2 January 2014 Revised 29 January 2014 Accepted 11 February 2014
This study tested the hypothesis suggesting that the preprocedural RDW predicts ISR in BMS in patients with stable and unstable angina pectoris.
Materials and methods We assessed clinical and angiographic data of the patients with normal renal function (serum creatinine < 1.3 mg/dl) who had undergone successful stent implantation from January 2008 through June 2013 at our institution. Only patients with stable and unstable angina who had undergone BMS implantation were included. The local ethics committee approved the study. Patients with unstable angina pectoris were defined according to the Braunwald classification [15]. As part of our preprocedural protocol, complete blood count and peripheral differentials had already been available before coronary angiography for all patients. Patients’ clinical and demographic characteristics including age, sex, coronary artery disease risk factors (arterial hypertension, diabetes mellitus, smoking, family history DOI: 10.1097/MCA.0000000000000105
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470 Coronary Artery Disease 2014, Vol 25 No 6
of coronary artery disease, dyslipidemia), creatinine, medications, and left ventricular ejection fraction were recorded. Coronary interventions were performed according to current practice guidelines and recorded in digital storage for quantitative analysis. Degree of coronary stenosis was estimated visually by experienced interventional cardiologists. A luminal narrowing 50% in a major subepicardial vessel (left anterior descending, left circumflex, or right coronary artery) was defined as significant stenosis. Target lesions were treated by elective PCI with coronary stent implantation. All patients received BMS. Direct stenting was applied as possible, but if indicated, balloon predilatation was performed before stent implantation, and if the primary angiographic result was not satisfactory, postdilatation was used. All patients received clopidogrel 600 mg at least 6 h before the stent implantation. Patients received weight-adjusted intravenous heparin before the intervention. Procedural success was defined as reduction of stenosis to less than 10% residual narrowing, with improvement in ischemic symptoms and without major procedure-related complications: death, emergency bypass surgery, or myocardial infarction (defined as greater than two times increase in creatine kinase-MB levels) [16]. ISR was defined as restenosis at the site of the stented lesion within 5 mm proximal or distal to the stent edges (in segment), with greater than 50% narrowing of the lumen diameter according to the results of control coronary angiographies [17]. Aspirin (100 mg/day) was administered indefinitely; clopidogrel 75 mg daily was continued for at least 6 months after the intervention. For patients’ data, we gained access retrospectively to the data at the time of interest when the patients with normal renal function underwent coronary stent implantation and then control coronary angiography was performed because of anginal symptoms and positive treadmill test results, thus recalling clinical, angiographic, and laboratory characteristics at that time. As such, we were able to collect the data for 663 patients. Patients were excluded from analysis if they had undergone drugeluting stent implantation (n = 221), had hemoglobin level less than 12 g/dl (n = 158), and had clinical evidence of cancer (n = 5), chronic inflammatory disease (n = 2), or any active infectious disease (n = 8), leaving 269 patients to be included in the study. Intraobserver and interobserver variabilities of stent restenosis analysis were assessed in a subset of 50 patients. Interpretations of the two investigators on the presence or absence of ISR agreed in 92% (62 of 71) and 96% (67 of 71), respectively. Intraobserver variability was assessed by one investigator. The two readings were concordant for the presence or absence of ISR in 95% (66 of 72) and 96% (67 of 71), respectively.
Hematological parameters, including hemoglobin, RDW, and platelet count, were analyzed by Cell-Dyn 3700 (Abbott Laboratories, Abbott Park, Illinois, USA).
Statistical analysis
Continuous variables are expressed as mean±SD. Categorical variables are expressed as percentages. To compare parametric continuous variables, Student’s t-test was used; to compare nonparametric continuous variables, the Mann–Whitney U-test was used; and to compare categorical variables, the w2-test was used. Multivariate logistic regression analysis was used to identify the independent predictor of ISR. All variables showing significance values less than 0.05 on univariate analysis (current smoking, diabetes mellitus, stent length, preprocedural RDW, period between two coronary angiographies) were included in this model. Two-tailed P values less than 0.05 were considered significant and the confidence interval was 95%. All statistical studies were carried out using the SPSS program (version 15.0; SPSS Inc., Chicago, Illinois, USA).
Results In the study population, mean age was 62±11 years; clinical and procedural data of the population according to with ISR and without ISR (n = 131 and 138, respectively) are presented in Table 1. There were no significant differences in sex, age, medications, hemoglobin, and platelet levels, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol, and left ventricular ejection fraction between the 138 patients without ISR and the 131 patients with ISR. The lesion characteristics and angioplasty procedural variables were identical in both patient groups, except for stent length. Stent length was significantly longer in patients with than those without restenosis (17.9±5.6 vs. 16.2±5.2 mm, respectively, P = 0.03). Compared with patients with restenosis, patients without restenosis had a significantly short period between two coronary angiographies (9.8±9.3 vs. 12.9±11.6 months, respectively, P = 0.02) and lower triglyceride levels (133±53 vs. 168±121 mg/dl, respectively, P = 0.05) (Table 1). Patients with ISR were more diabetic and had higher smoking rates (61 vs. 28 patients, P = 0.001, and 58 vs. 44 patients, P = 0.04). Preprocedural RDW was significantly higher in patients with ISR than those without restenosis (14.6±3.2 vs. 13.4±1.6%, P < 0.001). If RDW was included in univariate analysis as a qualitative variable, RDW levels of at least 13.0% were also associated with increased ISR (P < 0.001). CRP levels were similar between the two groups. However, in subgroup analysis, CRP levels were significantly higher in the unstable angina group and associated with increased ISR in this subgroup (3.1±2.4 vs. 2.1±2.2 mg/l, P = 0.03).
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Prediction of stent restenosis Yıldız et al. 471
Table 1
Variables of the patients with in-stent restenosis versus without in-stent restenosis With ISR (n = 131)
Without ISR (n = 138)
103 (79) 61.9±11.0 65.8±8.2 58 (44) 45 (34) 61 (46) 76 (58)
100 (73) 61.3±10.7 63.5±8.6 44 (32) 51 (37) 28 (20) 75 (54)
0.67 0.51 0.72 0.04 0.38 0.001 0.62
61 (47) 70 (53) 1.79±0.80 45 (34)
77 (56) 61 (44) 1.64±0.72 44 (32)
0.11 0.14 0.07 0.38
78 (59) 34 (26) 45 (34) 17.9±5.6 3.09±0.64
73 (53) 45 (33) 43 (31) 16.2±5.2 3.20±0.70
0.21 0.14 0.33 0.03 0.08
39 (30) 78 (68) 19 (15) 69 (53) 79 (60) 14.6±3.2 96±10 42±13 135±64 168±121 13.6±1.9 242±70 0.87±0.25 2.4±2.3 9.8±9.3
50 (36) 71 (51) 21 (15) 71 (51) 44 (32) 13.4±1.6 89±13 40±10 123±31 133±53 14.1±1.6 254±80 0.88±0.22 2.1±2.1 12.9±11.6
0.16 0.18 0.36 0.14 < 0.001 < 0.001 0.71 0.40 0.27 0.05 0.11 0.21 0.91 0.23 0.02
Male sex [n (%)] Age (years) LVEF (%) Current smoker [n (%)] Family history of CAD [n (%)] Diabetes mellitus [n (%)] Hypertension [n (%)] Cause of stent implantation [n (%)] Stable angina pectoris Unstable angina pectoris Number of significantly diseased vessels/patients Multivessel intervention [n (%)] Coronary vessel treated [n (%)] Left anterior descending Circumflex Right Stent length (mm) Stent diameter (mm) In hospital medical treatment [n (%)] ACE-I/ARB b-Blocker Ca-canal blocker Statins RDW Z 13.0% [n (%)] RDW (%) Fasting glucose (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Hemoglobin (g/l) Platelet count (109/l) Creatinine (mg/dl) C-reactive protein (mg/l) Period between two coronary angiographies (months)
P
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; ISR, in-stent restenosis; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; RDW, red blood cell distribution width.
Multivariate logistic regression analysis according to the risk of in-stent restenosis
Table 2
Number of significantly diseased vessels/patients Period between two coronary angiographies Current smoker Stent segment length Diabetes mellitus RDW
OR
95% CI
P
1.4 0.98 1.24 1.08 1.19 1.4
0.99–1.98 0.95–1.98 0.32–0.97 1.03–1.13 0.26–0.77 1.18–1.67
0.06 0.09 0.04 0.007 0.004 0.001
CI, confidence interval; OR, odds ratio; RDW, red blood cell distribution width.
In multivariate logistic regression analysis, diabetes mellitus, stent length, preprocedural RDW, and current smoking independently predicted ISR (Table 2).
Discussion The results of this study show that preinterventional RDW levels independently predict BMS restenosis in patients with stable and unstable angina. In previous studies, the prognostic significance of RDW in various cardiovascular disease has been shown; the present study shows for the first time the close relationship between RDW and BMS restenosis [1–8]. In recent years, studies have consistently shown that RDW is closely related to the prognosis and long-term
adverse events of cardiovascular diseases [6–8]. The underlying mechanism of the relationship between high levels of RDW and cardiovascular disease is unclear. Inflammation plays an important role in the atherosclerotic process [18]. Inflammatory cytokines have been found to suppress the erythrocyte maturation; thus, juvenile erythrocytes enter into circulation [19]. In addition, elevated levels of neurohumoral mediators stimulate erythropoiesis, for example, angiotensin II may affect the erythroid progenitor cells with a direct stimulation [20]. These factors may increase the variability in circulation red cell sizes. The investigators showed a relationship between generalized inflammation and elevated levels of RDW and found an association of RDW with high-sensitive CRP and erythrocyte sedimentation rate, which are indicators of inflammation [21]. Previous studies have suggested that ISR was associated with increased levels of CRP, interleukin-6, and serum amyloid A protein before or after the procedure [22–25]. They also reported that the preprocedural CRP values appeared to be a powerful predictor of both early and late restenosis in patients undergoing coronary angioplasty and stent implantation [26–29]. Buffon et al. [26] showed a significant association between CRP and restenosis. Clinical restenosis developed in 63% of patients with high
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CRP levels and in 27% of those with normal CRP levels. Walter et al. [28] reported that patients with increased CRP levels had a significantly higher risk of ISR with a rate of 19% in the lowest tertile compared with 37 and 45% in the upper tertiles, respectively. In contrast to these findings, other studies did not show the predictive value of inflammatory markers on ISR. Dibra et al. [29] and Delhaye et al. [30] showed that angiographic ISR was observed at similar rates in patients with elevated CRP levels compared with patients with normal levels. In the present study, our results suggested that preprocedural CRP levels did not predict clinical restenosis. However, in subgroup analysis, CRP levels were significantly higher in the unstable angina group and associated with ISR. Differences in the pathobiology between stable and unstable coronary syndromes and the widespread use of statins with anti-inflammatory and pleitrophic activity in our cohort of patients most likely explain our findings. In a recent study, Turak et al. [31] showed that a high preprocedural neutrophil-to-lymphocyte ratio significantly predicts BMS restenosis in patients with stable and unstable angina pectoris. In the present study, we did not assess the neutrophil : lymphocyte ratio as a marker of restenosis. Although the present study confirms the predictive role of known risk factors for restenosis, such as diabetes mellitus and stent length, it also shows a strong association between RDW and ISR, which has not been reported before. RDW remained a strong independent predictor of ISR even after adjustment for all other risk factors in multivariate analysis. Only hemoglobin levels were measured in this study. Iron levels, vitamin B12, and folate, which may affect RDW levels, were not measured. However, we did not enroll patients with anemia in our study. We believe that this makes it highly unlikely that the predictive value of RDW was related to iron deficiency. Furthermore, the incidence of clinically significant vitamin B12 and folate deficiency is low in a modern population. In a large-scale study, it was found that RDW was an independent predictor of mortality and the investigators concluded that the relationship between RDW and mortality was not confounded by anemia-related deficiencies such as vitamin B12, folate, and iron [32]. In previous studies, the restenosis rates reported within 6 months in patients with BMS ranged between 16 and 44% [33,34]. However, in the present study, our results suggested that BMS restenosis developed in 131 patients (48.7%). We followed up the patients with BMS 9.8±9.3 months. In agreement with our study, Mohan and Dhall [35] reported that BMS restenosis was 48.8% 6–9 months after the interventional procedure. Therefore, the higher stent restenosis rate may be related to the longer follow-up period. In addition, previous studies
have shown that exercise-induced angina at follow-up and a positive exercise treadmill test independently predict restenosis [36]. A pooled analysis of 15 treadmill studies involving 2250 patients with angiographic follow-up showed a 50% positive predictive value and a 76% negative predictive value for the exercise treadmill test [37–41]. In our study, control coronary angiography was performed in patients who had anginal symptoms and positive treadmill test results. We did not perform routine coronary angiography in all stented patients. Therefore, the high restenosis rate in the present study may be related to this factor. Another factor that may have led to overestimation of coronary stenosis in our population was the method of assessment of stenosis. We used visual interpretation instead of qualitative coronary angiography, which allows more accurate estimation of coronary artery stenosis. In a recent study, Nallamothu et al. [42] showed that physicians tended to assess coronary lesions treated with PCI as more severe than measurements by qualitative coronary angiography. Limitations
Our study was carried out on a retrospective basis and represented a single-center experience. The definition of stenosis was based on visual assessments, not on quantitative measurements. Before a procedure, a single blood sample does not anticipate the persistence of RDW over time. The second limitation is that the study was carried out in terms of BMS, and thus these results cannot be directly extrapolated to patients receiving drug-eluting stents. Conclusion
The present study confirms that preinterventional RDW predicts the risk of BMS restenosis in patients with stable and unstable angina pectoris, and may represent a useful screening tool to stratify patients according to the risk of future ISR after stent implantation and may influence clinical management.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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