C-reactive protein to albumin ratio and radial artery thrombosis post transradial angiography

Abstract

Aim: The aim is to evaluate the relationship between C-reactive protein (CRP) to albumin ratio (CAR) and radial artery thrombosis in patients undergoing radial angiography.

Patients & methods: We prospectively included 261 consecutive patients undergoing radial angiography, assessing radial artery diameter and thrombosis presence.

Results: The CRP values were significantly higher in radial artery thrombosis group compared with group without thrombosis (13.01 vs. 4.33 mg/l, p < 0.001, respectively). Also CAR was statistically significantly different between the group with thrombosis and the group without thrombosis (0.102 vs. 0.349, p < 0.001).

Conclusion: Our study is the first to assess CAR in radial thrombus development post-procedure in patients undergoing radial angiography. CAR can be useful in determining radial artery thrombosis after the coronary angiography.

Plain language summary

Summary points.

• Cardiovascular diseases stand as one of the leading causes of mortality, with coronary angiography widely acknowledged as the gold standard method for diagnosing coronary artery disease.

• Many studies have shown the radial approach's advantages over the femoral approach, particularly in reducing bleeding, vascular access complications and cardiovascular events.

• Many complications can occur, such as radial artery spasm, hematoma, dissection, arteriovenous fistula, aneurysm and occlusion, as a result of the increased use of the radial approach. Radial artery occlusion is the most common complication of TRA.

• Histopathological examination of the plug from the occluded radial artery reveals a rapidly organizing thrombus.

• The CRP/albumin ratio (CAR) has been proposed as a more sensitive indicator for the severity of inflammatory reactions and disease progression.

• In cases of radial artery thrombosis (RAT), while the impact of inflammation is recognized, there is currently no study investigating its correlation with parameters assessing inflammation. This study aims to evaluate the relationship between RAT and the severity of inflammation.

• In our study, CAR was found to be higher in patients who developed radial artery thrombosis.

• CAR has been identified as independent risk factors for RAT.

• The study has certain limitations such as a small sample size, absence of factors such as the number of puncture and patent hemostasis affecting radial thrombosis formation.

• In order to evaluate CAO as a predictor of RAT formation and to generalize the results to the whole population, larger-scale, randomized and multicenter studies that include all parameters that may affect the development of RAT are needed.

One of the leading causes of mortality today is cardiovascular diseases. Coronary angiography is considered the gold standard method for diagnosing coronary artery disease. Both transfemoral and transradial approaches are commonly used in diagnostic coronary angiography and percutaneous coronary interventions. Since the first radial approach angiography was performed in 1989, interest in radial access for interventions has increased.

Since then, numerous studies have demonstrated various advantages of the radial approach over the femoral approach, particularly with regard to reduction in bleeding, vascular access complications and cardiovascular events [1–3]. Due to increasing data emphasizing its tolerability, reliability and cost–effectiveness, the importance of radial access is on the rise [4]. An increase in the number of radial approaches has also led to an increase in complications associated with it. Many complications can occur, such as radial artery spasm, hematoma, dissection, arteriovenous fistula, aneurysm and occlusion, as a result of the increased use of the radial approach. In approximately 5–10% of cases, radial artery occlusion (RAO) is observed [5].

Our knowledge regarding the clinical approach, optimal treatment methods and predictors for occlusion remains insufficient. Puncture, during the delivery of the radial sheath and catheter manipulations can lead to dissections in the arterial wall strata and aseptic reactive inflammatory response, intimal hyperplasia and often intima-media thickening in the distal segments. Histopathological examination of the plug from the occluded radial artery reveals a rapidly organizing thrombus [6–8]. Several laboratory parameters are utilized to assess inflammation. C-reactive protein (CRP), a sensitive marker of inflammation, is a positive acute-phase reactant. Similarly, albumin decreases in inflammatory conditions as a negative acute-phase reactant [9].

In this context, the CRP/albumin ratio (CAR) has been proposed as a more sensitive indicator for the severity of inflammatory reactions and disease progression [9]. For example, it has been demonstrated that CAR can be utilized in evaluating the risk of stent restenosis [10]. In another study, it has been shown that it could serve as an indicator of the severity of coronary artery disease [11] In cases of radial artery thrombosis (RAT), the condition can start with arm pain and, rarely, progress to ischemia. In cases of radial artery thrombosis (RAT), the impact of inflammation is known, but there is no study investigating its relationship with parameters assessing inflammation. The aim of this study is to evaluate the relationship between RAT and the severity of inflammation. This will help reduce the factors that cause inflammation before thrombosis develops, thus decreasing the risk of thrombosis and reducing complications associated with thrombosis.

1. Materials & methods

1.1. Study population

This is a prospective, cross-sectional and observational study that included 261 consecutive CCS patients who underwent radial angiography at a tertiary heart center's outpatient clinic between October 2022 and March 2023. Patients with the following conditions were excluded from the study: concurrent autoimmune disease, chronic liver or kidney disease, mental retardation, inability to read and consent to the informed consent form, age under 18 years, active infection and the use of anticoagulant medications. This research was carried out in accordance with the Declaration of Helsinki and approval was obtained from the Ethics Committee of the Ankara Bilkent City Hospital (E1-22-3067). Radial artery thrombosis group and group without thrombosis gave informed consent before inclusion in the study.

1.2. Radial artery cannulation & laboratory data

Fasting blood glucose levels were examined for all patients included in the study. Liver and kidney function tests and complete blood counts were conducted. The body surface area was calculated using the Mosteller formula. Additionally, C-reactive protein (CRP) levels were assessed for all patients. Radial angiography was performed on the patients by multiple cardiologists. Patients who underwent successful transradial procedures were included in the study. A 6 French (F) radial sheath was used for all patients. After local subcutaneous anesthesia with 1% lidocaine, radial artery puncture was performed using a specialized radial cannulation needle and guidewire. After the sheath was placed, 200 mcg of nitroglycerin and 5000 IU of heparin were administered routinely. In case of proceeding to percutaneous coronary intervention, an additional 100 IU/kg of heparin was given before. Immediately after the procedure, the radial sheath was removed and manual compression was applied.

1.3. Transradial coronary angiography

CAG procedures were performed by randomly selecting three operators experienced in radial angiography. The catheters used for coronary angiography were 6F catheters. If a decision for revascularization was made during angiography, percutaneous coronary intervention was performed in the same session. An additional 100 IU/kg of heparin was administered. The introducer was removed immediately after the procedure by a registered and trained nurse. Hemostasis was achieved through manual compression and pressure dressing. Patients who underwent percutaneous coronary procedures were discharged the following day, whereas those who did not undergo the procedure were discharged after 4 h, following radial pulse assessment and bleeding control.

1.4. Assessment with doppler ultrasonography

Radial artery thrombosis was assessed using ultrasound 4 h after the procedure. All ultrasound examinations were performed by an experienced radiologist who was unaware of the catheterization procedure, using a multi-frequency linear probe ultrasound device. The forearm was held in a supine position, and the probe was placed parallel to the long axis. Color mode was used to identify the radial artery. The measurement of the radial artery diameter was typically performed at a point approximately 1 cm proximal to the styloid process, where the radial artery puncture was made. The radial artery diameter was calculated by taking measurements from inner wall to inner wall. The average of three measurements was calculated. In Doppler measurements, the absence of antegrade flow and the presence of a thrombus visualisation on ultrasonography were considered as radial thrombosis.

1.5. Statistical analyses

Statistical evaluation was performed using Statistical Package for Social Sciences (SPSS) for Windows 25 (IBM SPSS Inc., IL, USA) and Medcalc 11.4.2 (MedCalc Software, Mariakerke, Belgium) software programs. G-power analysis was employed using a t-test, with a significance level set at 80%. Assuming a medium effect size for the influence of Factor X, the effect size was set at 0.5. The normal distribution of the data was assessed using the Kolmogorov-Smirnov test. For numerical variables exhibiting normal distribution, the mean ± standard deviation was shown, while for those not displaying normal distribution, the median (interquartile range) was presented. Categorical variables were expressed in terms of count and percentage. For variables with non-normal distribution, the Mann–Whitney U test was employed for comparative analysis between two independent groups. The chi-square or Fisher's exact chi-square tests were used for comparing categorical variables. The diagnostic and prognostic values for radial thrombosis formation were evaluated using receiver operating characteristic (ROC) analysis. Binary logistic regression analyses were used to determine independent predictors of RAT. Variables, which might be a possible confounding factor or clinical relationship for RAT such as baseline demographic, laboratory and ultrasonographic variables were included in univariate analysis. The variables which were determined as p < 0.1 in univariate analysis were included in multivariate analysis. To avoid multicollinearity, we did not include CRP and CAR into the same multivariate regression model. p < 0.05 was considered statistically significant.

2. Results

Basal demographic features and laboratory findings of the study population are presented in Table 1. Patients were divided into two groups based on the presence of radial artery thrombosis: non-thrombosis group (n = 235), thrombosis group (n = 26). When demographic characteristics were compared, no significant differences were detected between the two groups in terms of age, gender, BMI and BSA. However, when looking at smoking, in the thrombosis group, a higher rate of smoking was observed compared with the non-thrombosis group (57.7 vs. 31.5%, p < 0.05). The two groups showed no substantial variations in the occurrence of diabetes, dyslipidemia, chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD). In the thrombosis group, a higher incidence of hypertension was observed compared with the non-thrombosis group (84.6 vs. 62.1%, p < 0.05). When assessing the incidence of low EF heart failure, it was found to be higher in the thrombosis group compared with the non-thrombosis group (19.2 vs. 5.9%, p < 0.05).

Table 1.

Demographic characteristics of the study population and laboratory parameters.

Variables	Non-thrombosis group (n = 235)	Thrombosis group (n = 26)	p-value
Demographic characteristics
Age, years (mean ± standard deviation)	62 ± 10	63 ± 10	0.574
Gender, male, n (%)	162 (68.9)	14 (46.2)	0.119
Body mass index, kg/m2	29.49 (15.78–49.22)	30.25 (23.42–45.35)	0.697
Body surface area, m2†	1.95 (1.39–2.62)	1.93 (1.57–2.38)	0.344
Comorbidities
Diabetes mellitus, n (%)	148 (37)	12 (46)	0.362
Hypertension, n (%)	146 (62)	22 (85)	0.023‡
Dyslipidemia, n (%)	39 (17)	2 (8)	0.392
Smoking, n (%)	37 (32)	15 (58)	0.007‡
Chronic obstructive pulmonary disease, n (%)	5 (2)	2 (1)	0.141
Coronary artery disease, n (%)	186 (79)	18 (69)	0.245
Low EF heart failure, n (%)	14 (6)	5 (19)	0.018‡
Medications used
Acetylsalicylic acid, n (%)	143 (55)	13 (50)	0.284
P2Y12 inhibitor, n (%)	44 (17)	0 (0)	0.011‡
Beta blocker, n (%)	130 (50)	14 (54)	0.886
RAAS, n (%)	125 (47)	13 (50)	0.774
Statin, n (%)	99 (38)	9 (35)	0.471
Calcium channel blocker, n (%)	49 (19)	4 (15)	0.517
Variables associated with radial angiography
Left radial approach, n (%)	209 (80)	24 (92)	0.749
Stent implantation performed	64 (24)	5 (19)	0.386
Radial artery diameter, cm	0.287 (0.200–0.400)	0.251 (0.150–0.330)	<0.001‡
Number of catheter uses	2 (1–4)	2 (1–4)	0.375
Echocardiography-related variables
Ejection fraction, %	55.43 (15–65)	51.64 (25–65)	0.168
LVED, cm	4.74 (3.70–7.50)	4.83 (3.60–6.40)	0.307
İVS thickness, cm	1.07 (0.70–1.70)	1.08 (0.70–1.49)	0.615
LVPW thickness, cm	1.03(0.70–3.30)	1.02 (0.70–1.20)	0.791
Left atrial diameter, cm	3.7 (2,10–6.30)	3.7 (2.80–4.70)	0.979
Laboratory parameters
Glucose (mg/dl)	130 (58–370)	135 (75–266)	0.767
Urea (mg/dl)	34 (6–75)	32 (12–83)	0.130
Albumin (mg/dl)	43 (20–58)	44 (26–70)	0.825
Creatinine (mg/dl)	0.86 (0.51–1.65)	0.89 (0.47–2.38)	0.146
Total cholesterol (mg/dl)	180 (80–370)	187 (103–279)	0.357
LDL (mg/dl)	103 (24–281)	108 (43–195)	0.489
HDL (mg/dl)	43 (20–78)	44 (22–71)	0.767
Triglyceride (mg/dl)	181 (34–805)	189 (52–539)	0.608
C-reactive protein (mg/dl)	4.33(0.0001–51)	13.01 (1.0–83)	<0.001‡
Hemoglobin (g/dl)	14.14 (5–17.8)	13.7 (7.4–17.6)	0.239
WBC (K/ul) × 103)	7.40 (3.8–13.9)	7.5 (4.06–11.50)	0.853
Neutrophil (K/ul) × 103	6.15 (1.52–7.80)	4.57 (2.35–7.88)	0.998
Lymphocyte (K/ul) × 103	2.95 (0.38–1.51)	2.25 (0.84–3.80)	0.991
Platelet (K/ul) × 103	249 (149–540)	283 (175–485)	0.055
CRP to Albumin ratio	0.102 (0.00–0.154)	0.349 (0.024–2.564)	<0.001‡

^†Calculated using the Mosteller formula.

^‡p-value less than 0.05 was considered significant for statistical analyses.

%: percentage; EF: Ejection fraction; HDL: High-density lipoprotein cholesterol; İVS: Interventricular septum; LDL: Low-density lipoprotein cholesterol; LVED: Left ventricular end-diastolic diameter; LVPW: Left ventricular posterior wall; n: Number; RAAS: Renin-angiotensin-aldosterone system blockers; WBC: White blood cell.

When examining procedural parameters, there was no notable distinction observed in the intervention site location, stent implantation and the quantity of catheter usage between the two groups. In the thrombosis group, the median radial diameter length was 0.251 cm (0.150–0.330), while in the non-thrombosis group, the median was 0.287 cm (0.200–0.400), and a significant difference was observed between the two groups (p < 0.001). No significant difference was found between the two groups in terms of glucose, albumin, urea, creatinine, cholesterol values and hemogram parameters. When looking at the CRP/albumin ratio, a statistically significant difference was observed between the thrombosis and non-thrombosis groups (0.102 vs. 0.349, p < 0.001).

CAR to predict radial artery thrombosis demonstrated an AUC value 0.78 (95% CI: 0.71–0.85, p < 0.001). The cutoff value of CAR >0.1429 was found to have a sensitivity of 73% and specificity of 72% (Figure 1). In addition, the predictability of radial artery diameter for thrombosis formation, it was found that it predicts with 61% sensitivity and 69% specificity when a predictive value of 0.24 cm is taken (AUC: 0.72; 95% CI: 0.60–0.84; p < 0.001) (Figure 2).

Figure 1.

ROC curve analysis of the CRP to Albumin ratio for predicting thrombosis formation.

CRP: C-reactive protein; ROC: Receiver operating characteristic.

Figure 2.

ROC curve analysis of the radial artery diameter for predicting thrombosis formation.

ROC: Receiver operating characteristic.

In the univariate regression analyses, hypertension (odds ratio [OR]: 3.33, 95% CI: 1.11–9.97, p = 0.032), smoking (OR: 2.92, 95% CI: 1.28–6.67, p = 0.011), ejection fraction (OR: 0.95, 95% CI: 0.92–0.99, p = 0.038), radial artery diameter (OR: 0.74, 95% CI: 0.65–0.85, p < 0.001), CRP (OR: 1.06, 95% CI: 1.02–1.09, p < 0.001) and CAR (OR: 6.89, 95% CI: 1.87–25.16, p < 0.001) were related with RAT (Table 2). Subsequently, multivariate analysis was carried out to detect independent predictors of RAT. Ejection fraction, radial artery diameter and CAR were independently predictive of RAT significantly (OR: 0.95, 95% CI: 0.90–98, p = 0.042; OR: 0.76, 95% CI: 0.68–90, p < 0.001; OR: 4.56, 95% CI: 1.15–18.05, p = 0.03, respectively) (Table 3).

Table 2.

Independent predictors of radial artery thrombosis by univariate analyses.

Variables	Univariate
	Odds ratio (OR)	95% CI	p-value
Age	0.97	0.93–1.01	0.240
Gender (ref:female)	0.52	0.23–1.18	0.240
Dyslipidemia (ref:absent)	0.42	0.09–1.85	0.253
Hypertension (ref:absent)	3.33	1.11–9.97	0.032
Smoking (ref:absent)	2.92	1.28–6.67	0.011
CAD (ref:absent)	0.59	0.24–1.43	0.245
Albumin	1.01	0.92–1.10	0.821
Ejection fraction	0.95	0.92–0.99	0.038
Radial artery diameter	0.74	0.65–0.85	<0.001†
CRP	1.06	1.02–1.09	<0.001†
CRP to albumin ratio	6.89	1.87–25.16	<0.001†

^†p-value less than 0.05 was considered significant for statistical analyses.

CAD: Coronary artery disease; CRP: C-reactive protein.

Table 3.

Independent predictors of radial artery thrombosis by logistic regression analyses.

Variables	Multivariate
	Odds ratio (OR)	95% CI	p-value
Smoking (ref:absent)	0.95	0.89–5.79	0.085
Ejection fraction	0.95	0.90–0.98	0.042†
Radial artery diameter	0.76	0.68–0.90	<0.001†
CRP to albumin ratio	4.56	1.15–18.05	0.030†
Hypertension (ref:absent)	2.38	0.73–7.66	0.146

^†p-value less than 0.05 was considered significant for statistical analyses.

CRP: C-reactive protein: OR: Odds ratio.

3. Discussion

In our study, the RAT ratio was determined to be 9.9%. The incidence of RAT was found to be higher compared with other studies in the literature [5,12]. Because in our study, in addition to pulse examination, doppler ultrasonography was performed on all patients who underwent transradial angiography. Transradial angiography is increasingly preferred because it results in fewer bleeding complications compared with transfemoral [13,14]. From a clinical perspective, bleeding is extremely important because bleeding complications related to arterial puncture sites can create a more significant cause of mortality and morbidity, especially in cases where anticoagulants and antiplatelet drugs are used [15]. Radial artery occlusion (RAO) is the most common complication of TRA. Thrombosis is also considered the most common occlusive pathology [7]. There are many factors that serve as predictors of thrombosis formation. The radial artery diameter to sheath diameter ratio is one of the important predictors [16]. Especially in those with a ratio above one, the incidence of RAO is seen as 4%, while in those with a ratio below one, the incidence is seen as 13% [17]. However, in our study, since the same diameter radial sheath was used, RAT was found to be associated only with radial artery diameter. It has been thought that in patients with smaller radial artery diameter, the placement of the sheath leads to more vascular trauma. The placement of the sheath creates a thrombotic environment that can lead to local endothelial damage, intimal tears, medial dissections and cessation of blood flow in the radial artery, adversely reshaping its structure and function.

In our study, a significant relationship between smoking and RAT was detected. Smoking is associated with decreased vasodilation in response to reactive hyperemia, impaired arterial function and increased inflammatory response [18]. Cigarette smoking leads to a marked sympathetic stimulation, nicotine absorption affects central sympathetic mechanisms and it increases the release of norepinephrine from sympathetic nerve endings [19]. A significant decrease in radial artery compliance has been demonstrated with adrenergic stimulation [20].

While some studies in the literature have shown that hypertension reduces the occurrence of RAO, our study found that it increased the frequency of RAO. Hypertension may be an inflammatory condition, and there are studies indicating a higher incidence of hypertension in patients with elevated CRP levels [21]. On the other hand, high blood pressure levels can induce a proinflammatory response. Vascular remodeling in arteries which can be structural, mechanical or functional results in increased media thickness and narrowed lumen [22].

In studies related to radial artery occlusion, no significant relationship has been found between heart failure and RAT. However, in our study, a statistically significant difference was observed between RAT and low EF heart failure. There is evidence that in congestive heart failure, NO-dependent vasodilation in the forearm or radial artery is significantly reduced, indicating a marked endothelial dysfunction in this condition [23]. A decrease in cardiac contractility and output reduces peripheral blood flow volume and velocity, leading to the release of endothelial factors that could result in vascular smooth muscle contraction [24]. Stasis secondary to low cardiac output, and endothelial dysfunction arising from neurohormonal activation or systemic inflammation, also create a predisposition to thrombosis [25]. In our study, the association between low EF heart failure and RAT is thought to be related to such reasons.

As our study is the first to assess radial artery thrombosis with CAR, there is no existing literature on this topic. CAR is considered an important indicator of systemic inflammation [26]. In ischemic diseases such as stroke, myocardial infarction and peripheral artery disease, CRP levels emerge as significant predictors [27]. Additionally, it can be used to predict no-reflow and in-hospital mortality in patients undergoing percutaneous coronary intervention [28,29]. Many traditional laboratory parameters have been used, especially to assess the inflammatory process and determine cardiovascular risk. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), uric acid, monocyte/high-density lipoprotein cholesterol (HDL-C) ratio and mean platelet volume-to-lymphocyte ratio (MPVLR) have been shown to be associated with poor outcomes in patients with coronary artery disease [30]. C-reactive protein and albumin are also laboratory markers of systemic inflammation and therefore are associated with thrombosis. C-reactive protein is a positive acute-phase protein that increases in response to inflammation, while albumin is a negative acute-phase protein that decreases in response to inflammation [31]. CRP-Albumin ratio (CAR), an easily obtainable parameter from biochemical analysis, is a novel marker of systemic inflammation. In our study, CAR was found to be higher in patients who developed radial artery thrombosis (RAT). Since the inflammatory process is crucial in the formation of radial artery thrombosis (RAT), it has been determined that there is more thrombosis in those with a high CAR. Additionally, in the multivariate logistic regression analysis conducted, it has been identified as an independent predictor in the development of RAT. The CAR can play a significant role as a predictor for RAT, which is a significant complication that occurs after transradial angiography.

The present study has some limitations. First, the sample size is small and it is an observational study. Its prognostic impact was not evaluated. Evaluation of inflammatory parameters may be meaningful in terms of long-term prognosis. The number of punctures and patent hemostasis as factors affecting radial artery thrombus have also been evaluated in studies, but were not evaluated in our study. Hemostasis of the radial artery intervention area was achieved by manual compression and pressure dressing, which may affect patent hemostasis. Radial angiography complication rate may be affected by operator experience. The application of TRA by different operators may be a limitation. In order to evaluate CAO as a predictor of RAT formation and to generalize the results to the whole population, larger-scale, randomized and multicenter studies that include all parameters that may affect the development of RAT are needed. In the literature, radial artery ultrasonographies after angiography have been examined at more frequent intervals, while our study has only one ultrasonographic assessment.

4. Conclusion

Our study is the first to evaluate the CAR in the development of radial thrombus after the procedure in patients who underwent radial angiography. In our study, we observed elevated levels of CAR among patients who experienced radial artery thrombosis. It has been recognized as a independent predictor for the occurrence of RAT. CAR can be useful as a valuable indicator for detecting radial artery thrombosis following coronary angiography.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval and/or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.